TAP Vol 6 Issue 9 Supplement

A Harborside Press® PublicationA Supplement to The ASCO Post™

Editor-in-Chief, James O. Armitage, MD ASCOPost.com

VOLUME 6, ISSUE 10JUNE 10, 2015

SUPPLE M E NT

OncologyThe ASCO Post profiles leaders in cancer care and researchNarratives in

Andrew C. von Eschenbach, MD

Wyndham H. Wilson, MD, PhD

Lodovico Balducci, MD

John L. Marshall, MD

Sandra J. Horning, MDVincent T. DeVita, Jr, MD

Alan F. List, MD Robert C. Young, MD

Carolyn R. ‘Bo’ Aldigé Bruce A. Chabner, MD

Plus, a tribute to James F. Holland, MD, in celebration of his 90th birthday, pages 41–44

PAGE 2 The ASCO Post | JUNE 10, 2015 | SUPPLEMENT

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Disclosure information available at ASCOPost.com.

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJame Abraham, MD Cleveland Clinic

Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Joseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Harold J. Burstein, MD Dana-Farber Cancer Institute

Robert W. Carlson, MD National Comprehensive Cancer Network

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

Jay S. Cooper, MD Maimonides Medical Center

John Cox, DO Texas Oncology

E. David Crawford, MD University of Colorado

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Bishoy Morris Faltas, MD Weill Cornell Medical College

John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Continuum Cancer Centers of New York

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

William T. McGivney, PhD Philadelphia, Pennsylvania

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Lee S. Schwartzberg, MD University of Tennessee Health Science Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Jamie Von Roenn, MD American Society of Clinical Oncology

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

William C. Wood, MD Winship Cancer Institute, Emory University

International EditorsClement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Rakesh Chopra, MD Artemis Health Institute, Gurgaon, India

Nagi El-Saghir, MD American University of Beirut, Lebanon

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John F. Smyth, MD University of Edinburgh Edinburgh, Scotland

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Editorial Board

ASCOPost.com | JUNE 10, 2015 | SUPPLEMENT PAGE 3

Carolyn R. "Bo" Aldigé

Carolyn R. ‘Bo’ Aldigé Reflects on 30 Years of Cancer Prevention

In 1985, Carolyn R. “Bo” Aldigé founded the Prevent Cancer Foun-

dation in honor of her father, who had died the previous year of head and neck cancer. She started the Foundation in her kitchen with a typewriter, a sheath of carbon copy paper, and a telephone. “I quickly rented an office because a charitable foundation with a PO box address sounds kind of squirrely,” said Ms. Aldigé.

Ms. Aldigé remembers her father, Captain Edward Perry Richardson, as a larger-than-life World War II hero—and her hero, too. “He was a pilot who led missions over England and France in a B-26 bomber he named after my mother. I doubt she knew its nickname was the Widow-Maker,” said Ms. Al-digé, adding, “Daddy was a member of the first squadron of bombers to cross the English Channel on D-Day.”

Her father’s heroic career in the Army Air Corps, as it was then called, ended on a dramatic note. “Daddy bad-ly injured his back jumping off the burn-ing wing of a plane that had crashed in France,” explained Ms. Aldigé.

Ironically, the founder of one of the country’s most noted cancer prevention foundations grew up in Reidsville, North Carolina, home of Lucky Strike cigarettes. Ms. Aldigé commented, “When you drove into town, a big billboard cautioned: ‘Qui-et please! Tobacco asleep.’”

It was a time of prolific smoking by a population unaware of the health dangers posed by tobacco consump-tion. “My father was born in 1918 and started smoking regularly when he was 13. He used to tell stories about going down to the cigarette factory and disabling the gizmos that cut the cigarettes into lengths, so that he and his buddy came out with yard-long smokes.”

Family History and Wanderlust

Ms. Aldigé’s family history reaches back to our nation’s tumultuous for-mative years. She was named for her great-grandmother, Elizabeth Caroline Perry, who was the granddaughter of Commodore Matthew C. Perry, the commander of a fleet of “Black Ships” that sailed into what is now Tokyo Bay in 1853, forcing Japan to open its doors to the rest of the world and ending the country’s centuries of isolationism.

“He’s a footnote in the history of

this country, but the Japanese revere his memory. My family history is a great icebreaker in a country that plac-es incredible value on ancestry,” said Ms. Aldigé.

Ms. Aldigé described her child-hood as typical for the time she grew up in. But although she enjoyed her hometown, friends, and family, she was gripped by an urge to see the far-flung places of the world.

“I learned about the world through playing board games and poring over history books, encyclopedias, and at-lases. I remember a book I received when I was in fifth grade, the Book of Marvels by Richard Halliburton. From then on, I wanted to see Ma-chu Picchu, the Pyramids, and the Taj Mahal,” said Ms. Aldigé.

At 10, she even sent handwritten letters to the state tourist bureaus of all 50 states, requesting tourist informa-tion. “I loved getting all the brochures and publications,” noted Ms. Aldigé.

She continued, “Despite my wan-derlust, I never even got off the East Coast until I was in college. I didn’t have my first plane ride until I was 12, and I didn’t fly again until I was 17. Now I can’t seem to get off them!”

Early Love of ScienceEducation was the centerpiece

of Ms. Aldigé’s family life; in fact, her paternal grandmother, born in 1885, graduated from college, a rarity for women in that period. Ms. Aldigé described herself as a

conscientious student with an in-satiable appetite for books. After completing high school, she entered an all women’s college in Virginia, Randolph–Macon Woman’s College, renowned for its high academic and liberal arts standards. “I majored in biology and chemistry, with a minor in art history. But the first subject that ever stymied me was calculus. I took it in my freshman year, getting the first B of my life.”

Despite her frustrating run-in with calculus, Ms. Aldigé excelled in col-lege and enjoyed the rigors and chal-lenges of academic life. Although she was pulled toward science, she didn’t have a solid notion about her career path. She recalled a conversation with the chairman of the biology de-partment, who was also the advisor for her senior thesis. “The chairman asked me what I wanted to do eventu-ally, and I just blurted out: ‘Cure can-cer.’ I had no idea why I said that. Nor did I have any idea at that point that I would wind up dedicating my pro-fessional life to preventing cancer. I was always interested in medicine but didn’t have the stomach for medical school,” said Ms. Aldigé.

After finishing undergraduate school, Ms. Aldigé spent the next 8 years working in research labs, which she found exceedingly tedious. Plus, there was no travel involved. “It was before we had kids, so my husband and I would save up all our vacation time and take trips to Europe. When the children started coming along, we traded Europe for vacation jaunts around the States,” said Ms. Aldigé.

Cancer Hits HomeIn 1984, Ms. Aldigé’s father was di-

agnosed with head and neck cancer. “My two young children and I moved in with my father to take care of him. I drove him to his radiation treatments

continued on page 6

NAME: Carolyn R. “Bo” Aldigé

TITLE: President and Founder, Prevent Cancer Foundation

NOTABLE HONORS: President, National Coalition for Cancer Research (1998–2006); Pioneer Award in Cancer Prevention, National Cancer Institute (1999); Howard University Legacy of Leadership Award (2000); American Association for Cancer Research Public Service Award (2004); George Washington University Cancer Institute Cancer Advocacy Award (2005); Partners in Progress Award, American Society of Clinical Oncology (2005); American Society of Preventive Oncology Distinguished Service Award (2006); membership on boards/advisory boards of the MD Anderson Cancer Center, the Vanderbilt-Ingram Cancer Center, and the Georgetown/Lombardi Cancer Center

Every grant [the Prevent Cancer Foundation makes] is a high point because I know we are potentially helping a

young scientist establish a career and make an advance in the science of cancer prevention and early detection.

— Carolyn R. ‘Bo’ Aldigé

When overlooked, hyperactivation of the PI3K-mTOR pathway drivesresistance to endocrine monotherapy and HR+ disease progression1,2

HAVE YOU LEFT YOUR PATIENTS VULNERABLE TO PI3K-mTORSIGNALING?

• PI3K-mTOR is the most common aberrantly activated pathway in breast cancer, with genetic defects occurring in >70% of cases2,3

• The PI3K-mTOR pathway is a major source of resistance and progression in HR+ advanced breast cancer1,2

• Novartis is committed to realizing the full therapeutic potential of targeting the PI3K-mTOR pathway for patients with HR+ advanced breast cancer

HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin.

References: 1. Miller T. Endocrine resistance: what do we know? Am Soc Clin Oncol Educ Book. 2013:e37-e42. 2. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224-235. 3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-215.

IN APPROACHING HR+ ADVANCED BREAST CANCER

The PI3K-mTOR pathway is an important component to consider in approaching HR+ advanced breast cancer. Find out more at TargetingPI3K-mTOR.com.

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2015 Novartis Printed in USA 4/15 BST-1114258

AFINIF-7278_M03_ASCO_Unbranded_SPD_JA.indd All Pages 4/30/15 6:00 PM

https://www.novartis.com

When overlooked, hyperactivation of the PI3K-mTOR pathway drivesresistance to endocrine monotherapy and HR+ disease progression1,2

HAVE YOU LEFT YOUR PATIENTS VULNERABLE TO PI3K-mTORSIGNALING?

• PI3K-mTOR is the most common aberrantly activated pathway in breast cancer, with genetic defects occurring in >70% of cases2,3

• The PI3K-mTOR pathway is a major source of resistance and progression in HR+ advanced breast cancer1,2

• Novartis is committed to realizing the full therapeutic potential of targeting the PI3K-mTOR pathway for patients with HR+ advanced breast cancer

HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin.

References: 1. Miller T. Endocrine resistance: what do we know? Am Soc Clin Oncol Educ Book. 2013:e37-e42. 2. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224-235. 3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-215.

IN APPROACHING HR+ ADVANCED BREAST CANCER

The PI3K-mTOR pathway is an important component to consider in approaching HR+ advanced breast cancer. Find out more at TargetingPI3K-mTOR.com.

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2015 Novartis Printed in USA 4/15 BST-1114258

AFINIF-7278_M03_ASCO_Unbranded_SPD_JA.indd All Pages 4/30/15 6:00 PM


and cared for him up until he died, which was on my mother’s birthday, August 1, 1984,” said Ms. Aldigé.

Ms. Aldigé took her father’s death hard. She spent a year in anger-lock, but then she resolved to learn more about cancer prevention, a field that was sorely neglected at the time. “The more I studied, the more I realized that much of cancer was lifestyle-driven, so it was largely a preventable disease. I was sitting at my kitchen table when I had my ah-ha moment. No other organization had a singu-lar focus on cancer prevention and early detection; everyone at the time seemed to be looking for the magic bullet to cure cancer.

“I’d never worked in an office and didn’t know how to use a computer. But I knew there was a huge unmet need in cancer prevention and wanted to make a difference. That’s when the Foundation was born. I incorporated Prevent Cancer Foundation on De-cember 3, 1985, about a year after my father died of cancer,” said Ms. Aldigé.

From the Ground UpThe first thing a fledgling founda-

tion needs is a board of directors. “I

Carolyn R. ‘Bo’ Aldigécontinued from page 3

called everyone I knew who would be a good fit for the Foundation’s board. All I asked was that they believe in me, and they did. At our first meeting, we began listing potential doctors to cre-ate a medical advisory board. That’s how it started,” said Ms. Aldigé.

She stressed that their priority was to fund research and support the careers of promising young inves-tigators who were working in can-cer prevention and early detection. “Our first grant was within our first year (1986), which was supplemen-tal funding to a fourth-year National Cancer Institute (NCI) fellow. It was a big deal for him. He had a family and couldn’t survive on the govern-ment stipend. He later went on to have an illustrious career at St. Jude’s Children’s Research Hospital.”

From that first fellow, the Prevent Cancer Foundation has continued to fund the careers of young can-cer investigators, realizing that it is money well spent, with huge down-stream dividends. “Every grant we make is a high point because I know we are potentially helping a young scientist establish a career and make an advance in the science of cancer prevention and early detection,” said Ms. Aldigé.

Despite Progress, Much Work Ahead

Asked for a reflection on her life’s work, Ms. Aldigé responded, “On one hand, I see a bright future, but on the oth-er, I’m discouraged. The future is bright because of the progress that it is being made every day on so many levels, in-cluding the access that more people now have to quality health care. The number of cancer survivors is increasing every year. The Affordable Care Act (ACA) covers recommended preventive services without co-pays. That’s all good. But I’m discouraged by the shrinking oncology workforce and certain unhelpful changes brought about through the ACA, such as the reduction of community-based phy-sician practices. I’m also discouraged that the budgets for the National Institutes of Health (NIH) and NCI are declining—and that so little of the nation’s total out-lay on health care is spent on prevention.”

Ms. Aldigé added, “What discour-ages me most is that we have the ability to reduce cancer incidence and death by 50% with what we know right now—but too many people are being diagnosed with cancer and dying of the disease.”

Global Perspective on CancerDespite the demands of her ca-

reer, her wanderlust is in full bloom.

Over the past 15 years, Ms. Aldigé has made a point of visiting at least one new country every year and has so far ventured to more than 50 dif-ferent nations around the globe, showing no signs of slowing down. In fact, at the time of this interview, she was preparing to leave for Belize and Guatemala and plans to travel to Spain, Croatia, and Istanbul, all be-fore the end of the year.

“Traveling around the world has given me a global perspective on can-cer, making me more sensitive to the issues of disparity of care and the value of our precious resources. Addressing global health inequity has become a passion of mine,” said Ms. Aldigé.

A last thought—one that puts the big picture into perspective—from a dedicated globe-trotting humani-tarian who has been battling at the frontlines of cancer prevention for more than three decades: “We have two little grandsons, and not a month has gone by that I have not spent time with them. Those visits keep any daily frustrations in perspective; we have to make the world they grow up in a bet-ter place, and that includes keeping people from getting cancer or helping them detect it early, when it can be suc-cessfully treated.” n

The ASCO Post Recognizes

June 7, 2015


At the 2007 ASCO Annual Meet-ing, Lodovico Balducci, MD,

received the inaugural B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology. Called the “patriarch of geriatric oncology,” Dr. Balducci is widely known in the oncology community for his warm humor and thick Italian accent. “My elderly cancer patients like to talk, share things with me. I like to listen, and one of my greatest motivations is that they get comfort in speaking with me,” Dr. Balducci told The ASCO Post.

Dr. Balducci was born toward the end of World War II, on April 7, 1944, in the Northern Italian town of Borgonovo. After the war, his parents returned to his father’s hometown of Rimini, where Dr. Balducci was reared until the age of 18.

“When I grew up, Italy was a de-veloping country, and I remember the ruins of the war; Rimini was one of the war’s most bombed European cit-ies. At that time, the town doctor and the priest were revered. Doctors were also the wealthiest of the professional class, so early in my youth, I became enamored of the respect the field com-manded,” said Dr. Balducci.

Medical EducationDr. Balducci was raised in an aca-

demic household; both parents were teachers in the humanities. He noted

Lodovico Balducci, MD

‘Father of Geriatric Oncology’ Lodovico Balducci, MD, Unearthed a New Understanding of Aging’s Effect on Cancer Treatment

that his first inclination was to follow in his parents’ footsteps, but his child-hood experience with depression and loneliness informed his choice to pur-sue a career in medicine.

“I loved classical Greek and Roman studies, but given my somewhat with-drawn personality, I knew that a career in the classics would have inadver-tently made me withdraw even further. But in medicine, I would be forced to interact in very intimate relationships with colleagues and patients. In many ways, medicine served as a safety exit for me,” said Dr. Balducci.

He explained that unlike in the United States, in which students move from high school to college and, if they choose, on to graduate school, in Italy students go directly from high school to postgraduate school. Dr. Bal-ducci, with the support of his parents, ventured to Rome and attended the Catholic University to study medicine, which at the time was Italy’s only pri-vate medical school.

“Of course there were public medi-cal schools, but back then there was no entrance exam, so basically anyone who graduated high school could at-tend medical school. But the Catholic University had very stringent accep-tance criteria, and the opportunity for mentoring and advancing your career was much greater than in public uni-versities. A public university might have a graduating class of 4,000, while

at the Catholic University it was 150,” said Dr. Balducci, adding, “I also wanted to put a few miles between me and my hometown, for a number of reasons.”

Journey to the United StatesWhen deciding on a specialty, Dr.

Balducci first eliminated surgery, com-menting that he didn’t have the manual dexterity for the discipline. “I decided to pursue a career in endocrinology, but I decided to continue my career in the United States to get the best medi-cal education possible; medicine in Italy at that time lagged far behind that

in the United States,” said Dr. Balducci. His move to the United States was

waylaid, but the disappointment of having his plans stalled proved a bless-ing in disguise. “I flunked the English language exam necessary to be ac-cepted in an American institution, but while studying to retake the test, I met a woman who soon became my wife,” said Dr. Balducci.

After Dr. Balducci finished his obligatory military service, he and his young wife, who was also a doctor, left Italy. Their first stop was a small private hospital in Winnipeg, Canada, called Misericordia General Hospital. It was 1972. While working at Mi-sericordia, an opportunity opened up at the University of Mississippi Medical Center Cancer Institute, so the Balduccis left Canada, traveling

to Jackson, Mississippi, where they completed their residency training. “I was happy with the training I received at the University of Mississippi. It was still in the heated time of the civil rights movement, and of course Mis-sissippi was right in the middle of it. But everyone tried to go out of his way to be decent,” said Dr. Balducci.

A Conversion Takes PlaceOncology was still a nascent disci-

pline in the early 1970s, but Dr. Bal-ducci said his desire to enter the field was influenced by an elegant presen-tation by J. Tate Thigpen, MD. “I was

accepted for a fellowship at MD An-derson, but for a variety of reasons, I decided to stay at the University of Mississippi, where I immediately be-gan working in the laboratory, doing research on hematopoietic stem cells. I also started working at the VA Medi-cal Center, and that’s where my con-version, if you will, took place,” said Dr. Balducci.

His “conversion” was the realiza-tion that instead of practicing proce-dure-based medicine, he could use his human-interaction skills to care for older, very vulnerable cancer patients. It was, in a sense, one of the seminal times in a field that had no name: ge-riatric oncology. “It started almost in my subconscious, but little by little, as I worked with older patients at the

Aging is universal, but it occurs at different rates in different individuals, so it is poorly reflected in

chronological age. But even in healthy individuals, age is a risk factor for some acute complications of cancer

treatment. That’s why assessing and treating the geriatric patient must be done on a patient-by-patient basis.

— Lodovico Balducci, MD

NAME: Lodovico Balducci, MD

TITLE: Professor of Oncology and Chief of Geriatric Oncology at Moffitt Cancer Center

MEDICAL DEGREE: MD, Catholic University, Rome, Italy

NOTABLE HONORS: Sigismondo d’Oro, Rimini (2002); Paul Calabresi Memorial Lecture Award, International Society of Geriatric Oncology (2003); Physician of the Year, H. Lee Moffitt Cancer Center & Research Institute (2003); Outstanding Achievements in Clinical Research Award, Association of Community Cancer Centers (2006); B. J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology (2007)

continued on page 8


VA, I began to realize that older cancer patients had different needs from their younger counterparts. So, in that re-spect, my life’s career was discovered at the VA in Mississippi, a very long way from my hometown in Italy. It was des-tiny, I guess, because it was then that I decided to forge a path in geriatrics,” said Dr. Balducci.

After his fellowship, Dr. Balducci and his wife left the University of Mis-sissippi and traveled south to the Uni-versity of South Florida College of Medicine, where he became a Profes-sor of Oncology and Chief of Geriatric Oncology at Moffitt Cancer Center. “While working at the VA in Missis-sippi, I’d written extensively on geri-atric oncology, and the new CEO of Moffitt, John C. Ruckdeschel, MD, had seen my work and invited me to Mof-fitt. I agreed on the condition that he would let me start a geriatric oncology program. He did, and, as they say, the rest is history,” said Dr. Balducci.

Changing Perceptions, Saving Lives

Dr. Balducci’s groundbreaking work in geriatric oncology should be framed within its historical context. The field of oncology itself was new at the time Dr. Balducci began his work in geriat-rics; in fact, his initial geriatric program at Moffitt was the country’s first in the field. Oncologists had laser-like focus on treating patients with the latest che-motherapy drug, so changing percep-

tions about the biology and psychoso-cial needs of the older cancer patients was no small challenge. Asked about the oncology culture barriers he had to confront at the time, with typical mod-esty, Dr. Balducci replied, “Everyone was searching for a cure at that time; I was just going in a new direction.”

He explained that aging involves a progressive loss of the functional re-serve of multiple organ systems that over time develop into the so-called geriatric syndromes—conditions that are typical of, although not unique to, aging. “Aging is universal, but it oc-curs at different rates in different in-dividuals, so it is poorly reflected in chronologic age. But even in healthy individuals, age is a risk factor for some acute complications of cancer treatment. That’s why assessing and treating the geriatric patient must be done on a patient-by-patient basis,” said Dr. Balducci.

He continued, “For instance, I’m currently treating an 86-year-old woman with chronic myelogenous leukemia [CML], breast cancer, and a history of colon cancer. She’s also had a stroke, which has left her with left-sided paralysis for the past 10 years. And yet she is not ready men-tally to die. So, from a clinical stand-point, does she need chemotherapy for her breast cancer? We don’t know. But she definitely needs to continue treatment for the CML or she’ll die. My point is, there are no clinical tri-als that can tell a doctor how to treat this woman. You have to get close to

her and make critical decisions,” said Dr. Balducci.

Career MilestonesAlthough he has been working at

the forefront of oncology, caring and developing better ways to treat our oldest and most vulnerable patients, the energy in his voice could reflect that of an enthusiastic oncology fel-low. “My time at Moffitt has been the richest part of my career. I’ve had the privilege to work with wonder-fully talented and dedicated people, including an aggressive and talented nurse practitioner, Janine Overcash, who joined me when she was just out of school. And probably the best thing that happened was when Dr. Martine Extermann, a young fellow from Geneva, joined my geriatric program. She’s still here and is ac-tually the soul of our research pro-gram,” said Dr. Balducci.

Asked about the significant mile-stones reached during his career, Dr. Balducci responded, “The ability to assess a patient’s life expectancy with reasonable accuracy and to gauge one's ability to withstand treatment side ef-fects. At Moffitt, we have developed the CRASH score calculator to deter-mine the risk associated with treat-ments. Several other institutions have also contributed to this work.”

“Then there is the CALGB study published by Dr. Hyman Muss, which ended a controversy in the field by demonstrating that older women with breast cancer can benefit from adju-

vant chemotherapy. Hy, who is a dear friend, deserves a lot of credit for this important work,” said Dr. Balducci.

Dr. Balducci’s current clinical re-search activities address the manage-ment of frail older people, assessment of quality-of-life factors and prognos-tic indicators in older patients with cancer, and interactions of comorbid-ity and functional status in this pa-tient population. “Using prognostic tools and building on past work, we are looking at bringing the new trend of personalized chemotherapy into the geriatric setting to improve sur-vival and quality of life for our elderly patients. I think our current work is in line with the Affordable Care Act’s value over volume care initiative,” said Dr. Balducci.

Asked if he’s had any mentors who have made an impression on him along the way, he said, “I have three role models: my wife, who is Head of Geriatrics at the Tampa VA, Dr. Kathy Foley, who is a her-oine of mine, a person who has brought humanity back to oncology and eased suffering worldwide, and Dr. Patty Ganz, for her consistently novel approaches to quality of life,” said Dr. Balducci.

What does Dr. Balducci do to un-wind? “Well I don’t have much free time, but we have two wonderful grandchildren who live in New Or-leans whom we visit, probably more often than my son and his wife would like,” Dr. Balducci said jokingly, add-ing, “We also love opera, and I write when I have the time. Life is hectic but very rewarding.” n

Lodovico Balducci, MDcontinued from page 7

Visit The ASCO Post website at www.ASCOPost.com

News and Views from the World of Clinical Oncology and Hematology

CLIENT: Lilly FINISH SIZE: 21.75” wide x 14” high

JOB#: ELRALU 27020 (Tabloid) ARTIST: MC

LOCATION: Mechanicals COLLECT DATE:

R|O|U|T|I|N|G| |S|T|A|G|E M8ED CW AD CPM ACD AE inserv

SINCE THE APPROVAL OF DOCETAXEL IN 1999, NO SECOND-LINE REGIMEN HAS EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF METASTATIC NSCLC PATIENTS1-3

NSCLC=non-small cell lung cancer.

DID YOU KNOW?

B:14

.25

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T:14

in

T:10.875 in

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27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_TAB_M8.indd 2 1/9/15 6:29 PM


JOB#: ELRALU 27020 (Tabloid) ARTIST: MC



SINCE THE APPROVAL OF DOCETAXEL IN 1999, NO SECOND-LINE REGIMEN HAS EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF METASTATIC NSCLC PATIENTS1-3

NSCLC=non-small cell lung cancer.

DID YOU KNOW?

B:14

.25

in

B:11 inT:

14 in

T:10.875 inS:

13 in

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27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_TAB_M8.indd 2 1/9/15 6:29 PM

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0 3 6 9 12 15 18 21 24 27 30 33 36

TIME FROM RANDOMIZATION (MONTHS)

527 415 329 231 156 103628

625

CYRAMZA+ docetaxelPlacebo+ docetaxel 501 386 306 197 129 86

Number at Risk

70 45 23 11 2 0

56 36 23 9 0 0

CYRAMZA+ docetaxel

Placebo+ docetaxel

Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

10.5MONTHS

CYRAMZA+ docetaxel

(n=628)

Placebo+ docetaxel(n=625)

15% INCREASEIN MEDIAN OS

(9.5, 11.2)

MONTHS9.1

(8.4, 10.0)

OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) MAJOR OUTCOME MEASURE

VISIT www.CYRAMZAHCP.com

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC4

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively4

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001)

— The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively

• ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)*

CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate.

*ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.5 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253)The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.4

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLYSIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4

CYRAMZA is the first antiangiogenic agent FDA approvedin combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4

WARNING: HEMORRHAGECYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and PrecautionsHemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal

hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs)

including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension• An increased incidence of severe hypertension occurred in

patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across

clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.

Gastrointestinal Perforations• CYRAMZA is an antiangiogenic therapy that can increase the

risk of gastrointestinal perforation, a potentially fatal event. In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing• CYRAMZA has not been studied in patients with serious or

nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)• RPLS has been reported at a rate of <0.1% in clinical studies

with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Most Common Adverse Reactions• The most commonly reported adverse reactions (all grades; Grade

3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions• No pharmacokinetic interactions were observed between

ramucirumab and docetaxel.

Use in Specific Populations• Pregnancy Category C: Based on its mechanism of action,

CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page.

RB-L HCP ISI 17DEC2014

References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014. 4. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 5. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

RB93740 12/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.CYRAMZA® is a registered trademark of Eli Lilly and Company.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

NEW FDA APPROVAL

B:14.25 inB:14

.25

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B:11 in B:11 in

T:14 inT:14

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T:10.875 in T:10.875 in

S:13 inS:13

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S:9.5 in S:9.5 in

27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_TAB_M8.indd 3-4 1/9/15 6:29 PM

http://www.cyramzahcp.com/index.html?WT.srch=1&WT.mc_id=128809-1571486-267

OS

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ILIT

Y

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36

TIME FROM RANDOMIZATION (MONTHS)

527 415 329 231 156 103628

625

CYRAMZA+ docetaxelPlacebo+ docetaxel 501 386 306 197 129 86

Number at Risk

70 45 23 11 2 0

56 36 23 9 0 0

CYRAMZA+ docetaxel

Placebo+ docetaxel

Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

10.5MONTHS

CYRAMZA+ docetaxel

(n=628)

Placebo+ docetaxel(n=625)

15% INCREASEIN MEDIAN OS

(9.5, 11.2)

MONTHS9.1

(8.4, 10.0)

OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) MAJOR OUTCOME MEASURE

VISIT www.CYRAMZAHCP.com

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC4

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively4

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001)

— The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively

• ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)*

CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate.

*ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.5 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253)The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.4

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLYSIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4

CYRAMZA is the first antiangiogenic agent FDA approvedin combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4


Warnings and PrecautionsHemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal

hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs)

including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension• An increased incidence of severe hypertension occurred in

patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across

clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.

Gastrointestinal Perforations• CYRAMZA is an antiangiogenic therapy that can increase the

risk of gastrointestinal perforation, a potentially fatal event. In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing• CYRAMZA has not been studied in patients with serious or

nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)• RPLS has been reported at a rate of <0.1% in clinical studies

with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Most Common Adverse Reactions• The most commonly reported adverse reactions (all grades; Grade

3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions• No pharmacokinetic interactions were observed between

ramucirumab and docetaxel.

Use in Specific Populations• Pregnancy Category C: Based on its mechanism of action,

CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page.

RB-L HCP ISI 17DEC2014

References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014. 4. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 5. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

RB93740 12/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.CYRAMZA® is a registered trademark of Eli Lilly and Company.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

NEW FDA APPROVAL

B:14.25 inB:14

.25

in

B:11 in B:11 in

T:14 inT:14

in

T:10.875 in T:10.875 in

S:13 inS:13

in

S:9.5 in S:9.5 in

27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_TAB_M8.indd 3-4 1/9/15 6:29 PM

CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014 CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014

CYRAMZA RB-L HCP BS 17Dec2014 Brief Summary 9.5 x 13 PRINTER VERSION 1 OF 2

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.


INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA Administered in Combination with DocetaxelStudy 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than

in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA plus docetaxel (N=627) Placebo plus docetaxel (N=618)All Grades

(Frequency %) Grade 3-4

(Frequency %) All Grades


(Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10

Neutropenia 55 49 46 40

Thrombocytopenia 13 3 5 <1

Gastrointestinal Disorders Stomatitis/Mucosal inflammation

37 7 19 2

Eye Disorders Lacrimation increased 13 <1 5 0

General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11

Peripheral edema 16 0 9 <1

Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1

Vascular Disorders Hypertension 11 6 5 2

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category CRisk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST)


CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential FertilityAdvise females of reproductive potential that CYRAMZA may impair fertility. ContraceptionBased on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

DOSAGE AND ADMINISTRATION

Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR)• Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension• Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria• Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications• Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding• Permanently discontinue CYRAMZA.

For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA

Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 17Dec2014

T he ASCO Post remembers the fol-lowing specialists in oncology

who passed away in 2014–2015. Please write to [email protected] to recognize and pay tribute to others in a future issue.

Eddie Reed, MDDecember 17, 1953–May 28, 2014

Eddie Reed, MD, was a pioneer in the molecular pharmacology of DNA-damaging anticancer agents and the clinical development of paclitaxel for ovarian cancer. He graduated from Yale University School of Medicine

in 1979, completed his internship and residency at Stanford University in 1981, and was then accepted for a fel-lowship at the National Cancer Insti-tute (NCI).

From 1985 to 2001, he served in a variety of increasingly responsible roles at the NCI, culminating with his appointment as Chief of the Pharma-cology Branch and Chief of the Ovar-ian Cancer and Metastatic Prostate Cancer Clinic in the Division of Clin-ical Science, becoming the first Afri-can American branch chief to serve at the Institute.

Much of his clinical investigation centered on DNA damage and repair in cancer cells. Dr. Reed was also a re-nowned authority on the use of the an-ticancer agents paclitaxel and cisplatin.

Along with clinical research, Dr. Reed was deeply involved in many public health cancer prevention, screening, and control programs. In 2005, Dr. Reed was recruited to serve as Director of the Division of Can-cer Prevention and Control, Centers for Disease Control and Prevention (CDC).

In 2008, Dr. Reed joined the USA Mitchell Cancer Institute in Mobile, Alabama, where he served as Clini-cal Director while continuing his research that concentrated on mo-lecular pharmacology and clinical development of novel platinum com-

In Memoriam

pounds, with a chief focus on ovarian cancer and metastatic prostate cancer.

Dr. Reed was an active member of the American Association for Can-cer Research (AACR). In addition to serving as a member of the AACR Board of Directors from 2008 to 2011, he was elected as Chair of the AACR Minorities in Cancer Research Council, serving a term from 2009 to 2010.

He also served on the National Ad-visory Council on Minority Health and Health Disparities and on the In-stitute of Medicine’s National Cancer Policy Forum. He twice received the U.S. Public Health Service Commen-dation Medal.

In honor of Dr. Reed’s dedication and advocacy for underserved can-cer populations, his friends and col-leagues established the Dr. Eddie Reed Fellowship Program in Global Oncol-ogy. It will bring cancer care trainees from Africa to Massachusetts General Hospital and its collaborators at Har-vard University and other American academic centers. ❧

John Michael Fitzpatrick, MCh, FRSCIJuly 15, 1948–May 14, 2014

John Michael Fitzpatrick, MCh, FRSCI, was one of Europe’s most highly regarded medical opinion lead-ers. He studied medicine at Universi-ty College Dublin and did his clinical internship at St. Vincent’s Hospital in Dublin. While doing his residency at St. Vincent’s, he decided to become a urologist, and in 1977, seeing a need

to further his education as a surgeon, he moved to the Institute of Urology at St. Peter’s Hospital in London.

After completing his training in London, Dr. Fitzpatrick returned to Dublin in 1981 as a consultant urolo-gist and senior lecturer in urology in the Meath and St. James’ Hospitals


CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014 CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014


CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.


INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA Administered in Combination with DocetaxelStudy 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than

in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA plus docetaxel (N=627) Placebo plus docetaxel (N=618)All Grades


(Frequency %) All Grades


(Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10

Neutropenia 55 49 46 40

Thrombocytopenia 13 3 5 <1

Gastrointestinal Disorders Stomatitis/Mucosal inflammation

37 7 19 2

Eye Disorders Lacrimation increased 13 <1 5 0

General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11

Peripheral edema 16 0 9 <1

Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1

Vascular Disorders Hypertension 11 6 5 2

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category CRisk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST)


CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential FertilityAdvise females of reproductive potential that CYRAMZA may impair fertility. ContraceptionBased on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

DOSAGE AND ADMINISTRATION

Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR)• Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension• Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria• Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications• Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding• Permanently discontinue CYRAMZA.

For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA

Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 17Dec2014

Eddie Reed, MD

John Michael Fitzpatrick, MCh, FRSCI

continued on page 26


Bruce A. Chabner, MD

N umerous challenges and mile-stones mark the course of an

oncology career. Community doc-tors remember special patients, often speaking about a singular bond that is unique among a profession that deals with life and death daily. Researchers recount long hours of seeming futil-ity and then the inexplicable moment of a breakthrough that leads to a new compound. Doctors who move into government and leadership roles in academic institutions need abundant skills to finesse the complexity into a core mission. And there are oncolo-gists who selflessly venture to the poorer regions of the globe to deliver care to the most vulnerable of cancer patients. Then there are the select few whose career is a composite of all of the above. One such remarkable on-cologist is Bruce A. Chabner, MD.

Dr. Chabner grew up Shelbyville, Il-linois, a small farming community in the center of the Prairie State. “My father was a general practitioner in Shelbyville, which was a beautiful little town that I still visit frequently. My dad’s practice was based on whatever the needs of his patients were, from delivering babies to fixing broken bones and appendecto-mies. In the later part of his career, he fo-cused on internal medicine. His practice had a lot of influence on my becoming a doctor,” said Dr. Chabner.

Dr. Chabner continued, “I left Shelbyville after my third year of high

Bruce A. Chabner, MD, and His Innovative Pharmacology Research Led to the Development of Practice-Changing Therapies

school and went to Yale University, first with the intention of majoring in biol-ogy. But I became very interested in his-tory and spent the majority of my junior and senior years in the history depart-ment, with a focus on modern Euro-pean history and the territorial settle-ments of the Paris Peace Conference of 1919. Although I changed direction, my time in history was valuable, primarily because I learned to write.”

Early Career in Drug Development

After graduating summa cum laude from Yale in 1961, Dr. Chabner decided to follow in his father’s medi-cal footsteps and entered Harvard Medical School. “I was very inter-ested in pharmacology, which would help later on in my research career,” said Dr. Chabner. He graduated from Harvard, earning his MD degree in 1965, and then completed house staff training at the Peter Bent Brigham Hospital. In 1967, at the height of the Vietnam War, Dr. Chabner joined the National Cancer Institute (NCI) as a clinical associate. Serving at the NCI was an attractive alternative to mili-tary service and would also be a piv-otal point in his career.

“As I was getting ready to leave for the National Institutes of Health (NIH), my sister was diagnosed with a malignant thymoma. That event solidi-fied my decision to pursue a career in

oncology,” said Dr. Chabner.“The NIH was the most active place

in the country to learn about cancer drug development and early-phase clinical trials. I spent 2 very forma-tive years in the clinical service under the tutelage of Drs. Vince DeVita and George Canellos. I had a wonder-ful time there, learning about cancer, lymphomas, and experimental thera-peutics. That’s when I really became interested in biochemistry and bio-chemical pharmacology, learning how drugs worked and how drug resistance develops,” said Dr. Chabner.

Methotrexate ResearchAlthough methotrexate has been

used for more than 40 years, Dr. Chab-ner’s early pharmacologic research was essential for the full development of this agent as a clinically useful drug. “I left the NIH in 1969 and returned to Yale University to finish my residency. Then I spent a year in the pharmacology labo-ratory of Dr. Joseph Bertino, learning about enzymology and biochemistry. We purified and characterized an en-zyme called carboxypeptidase, which cleaves folates. Although carboxypep-tidase was originally conceived of as a treatment by way of folate depletion, it actually found another place in medi-cine as a rescue agent for methotrexate. It is now approved for cleaving metho-trexate in patients who have drug toxic-ity related to high-dose regimens, and was the first bacterial enzyme to be used therapeutically,” said Dr. Chabner.

In 1971, Dr. Chabner returned to the NCI as a Senior Investigator in the Laboratory of Clinical Pharmacology, where, among other research efforts, he continued investigations in the field of antifolate drug resistance. “At NCI, I immediately became involved in research related to the mechanism of activation and determinants of re-sponse related to antimetabolites, and in particular, the biochemistry of cy-tosine arabinoside. I continued to be interested in antifolates, particularly in the activation to polyglutamates and the pharmacokinetics in high-dose

therapy, and developed a method for monitoring drug levels. It is still used as standard part of high-dose methotrex-ate therapy,” said Dr. Chabner.

Dr. Chabner moved his discussion from the lab to the clinic. “We be-came very interested in non-Hodgkin lymphoma, and under Vince DeVita’s guidance, we developed active combi-nation chemotherapy regimens. Most of the regimens have changed, but the basic principles of combinations and the curability of the disease set the foundation for what we have today,” said Dr. Chabner.

Transformative Period at the NCI

In 1980, Dr. Chabner was named Associate Director of the Clinical Oncology Program and in 1982 suc-ceeded Dr. DeVita as Director of the Division of Cancer Treatment. “The

NAME: Bruce A. Chabner, MD

TITLE: Director Emeritus of Clinical Research, Massachusetts General Hospital Cancer Center

MEDICAL DEGREE: MD, Harvard Medical School

NOTABLE HONORS: Outstanding Service Medal, U.S. Public Health Service (1983); David A. Karnofsky Memorial Lectureship, American Society of Clinical Oncology (1985); Melville Jacobs Award, American Radium Society (1986); Bruce F. Cain Memorial Award, American Association for Cancer Research (1998); Pinedo Cancer Care Prize, Society for Translational Oncology (2006); Fellowship in the Academy of the American Association for Cancer Research (2015)

We can now get a drug into the clinic and see results immediately, sometimes after a phase I trial; the FDA

accelerated approval system didn’t exist back then. So the tradeoff of today’s extra paperwork burden is well worth it

in the long run. — Bruce A. Chabner, MD


Division was responsible for intramu-ral research, as well as the intramural clinical trials program, the NCI’s coop-erative group program, grants related to clinical trials, and drug develop-ment,” Dr. Chabner said.

During this very busy period, several important drugs were coming through the system, he confirmed. “One was cisplatin, which was being tested in a variety of diseases in cancer centers and the NCI’s cooperative group. The sec-ond compound of great interest was pa-clitaxel. It was discovered on contract with the NCI and presented a rather unique situation. There was no intel-lectual property patent for the taxanes. We had a lot of key data on its activity and use in the clinic, however, and we licensed it through a rather unique con-tract mechanism to Bristol-Myers. This became an important turning point in drug development because it became the first billion dollar cancer drug and that attracted the attention of the phar-maceutical industry,” said Dr. Chabner.

He continued, “The other area of great interest while I was at the NCI was in AIDS and AIDS drug develop-ment. Robert Gallo had isolated the virus that causes AIDS and developed the blood test to detect the virus in the division of cancer treatment. Then Sam Broder developed a screening sys-tem and discovered the first drug that was effective against HIV: AZT. AIDS drug development became an impor-tant part of our mission at NCI.”

After more than 27 years at the Na-tional Cancer Institute and 13 years as the Director of the NCI’s Division of Cancer Treatment, Dr. Chabner left the NIH in April 1995 to accept a new position at the Massachusetts General Hospital (MGH). “Since coming to Boston, I’ve been involved in much of the same kind of research activities that were pursued at the NIH. Howev-er, when I first arrived at MGH, we had the challenge of building a clinical ser-vice. I did that in partnership with the other Harvard hospitals and the Dana-Farber Cancer Institute. I was fortu-nate that a lot of talented people came to MGH in my early days there, work-ing with Daniel Haber, Tom Lynch, David Ryan, Jeff Engelman, and many others,” said Dr. Chabner.

Drug Development Then and Now

Asked to contrast the research envi-ronment of the NCI with the current setting, Dr. Chabner responded, “Well

it was very easy back then to take an idea into the clinic and write a proto-col and to quickly get it implemented into a study. There were very few barri-ers to conducting clinical research, and there was so much to learn. However, the U.S. Food and Drug Administra-tion (FDA) was rather skeptical and

slow at approving new cancer drugs in those days. So on one hand today’s review system is more complicated on the administrative side, but on the oth-er hand we have a more receptive FDA, which is partnering with industry and academic centers to advance more compounds through the pipeline.”

He added, “We can now get a drug into the clinic and see results immedi-ately, sometimes after a phase I trial; the FDA accelerated-approval system didn’t exist back then. So the tradeoff of today’s extra paperwork burden is well worth it in the long run.”


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Notable AchievementsDespite the demands of a long

career, Dr. Chabner shows no signs of slowing down. “I’m currently the emeritus director of the MGH Can-cer Center and have very limited ad-ministrative responsibilities. I’m in-volved in a large community outreach program sponsored by the Lazarex Cancer Foundation. I’m also part of an outreach program to establish can-cer treatment and control services in Botswana.”

He continued, “I lecture, teach, mentor fellows, and attend on the medical service. I have more time now for writing and for interacting with colleagues in industry and the gov-ernment on drug development issues. Over the years, Boston has become an international center for cancer drug development, both in biotechnology and large pharma.”

Over the course of his notable career, Dr. Chabner has received numerous awards and honors in recognition of his scientific achievements, including the David A.

Karnofsky Memorial Lectureship of the American Society of Clinical On-cology in 1985, the Melville Jacobs Award of the American Radium Soci-ety in 1986, the Bruce F. Cain Memo-rial Award of the American Associa-tion for Cancer Research (AACR) in 1998, and most recently, Fellowship in the Academy of the AACR in 2015.

Dr. Chabner was promoted to the flag rank of Rear Admiral in the Public Health Service (PHS) in 1991. He has received numerous public health awards and medals, including its highest award, the Distinguished Service Medal, which

was awarded for his contributions to the development of paclitaxel.

Dr. Chabner, a lifelong golfer, hits the links whenever there’s a weather-permitting window in his exhausting schedule. His favorite partners are his wife, Davi-Ellen (of 51 years), and mentor and fellow researcher, Dr. Joe Bertino, and Dr. Jay Loeffler, Chief of Radiology at MGH. He has what he describes as a terrific family: “Two wonderful children and their spouses, and five grandchildren are a lot of fun,” he said—the rewards of a life well lived. n

Bruce A. Chabner, MDcontinued from page 15

Vincent T. DeVita, Jr, MD

A s a young boy growing up in the Bronx, Vincent T. DeVita,

Jr, MD, admired the local iceman, a thick-muscled guy known as Nunzi, who used to carry a big block of ice on his shoulder with a set of tongs, and effortlessly slide it into the DeVitas’ icebox. “A friend once asked me what I wanted to be when I grew up, and I said an iceman like Nunzi. My mother was standing nearby. She panicked at the thought and said, ‘No way, Vin-cent wants to be a doctor.’ And from that day on I said I wanted to become a doctor and never deviated from that goal,” said Dr. DeVita.

Dr. DeVita speaks with a courtly, inward voice that belies the sense of power behind the man. But despite his long and illustrious career, he remem-bers where he came from. “I had a lot of guardian angels. Although I was a ca-pable student, my high school principal, a terrific man named Hank Richards, felt I was slipping a bit. He met with my mother and me and explained that I was fooling around too much, not working to my potential. I was impressed by the way he handled himself. It was a turning point, and I thank him to this day.”

Dr. DeVita ventured to college across the Mason-Dixon line at Wil-liam & Mary—a Southern culture

Pioneer in Combination Chemotherapy, Vincent T. DeVita, Jr, MD, Changed the Face of Modern Oncology

shock for the city-smart New Yorker. “I was a good student, finishing fourth in my freshman class. But in my sopho-more year, I joined a fraternity and started partying a bit too hard. A chem-istry professor, Alfred Armstrong, who was keeping his eye on me, stopped me one morning as I was crossing the campus. He gave me quite a lecture.

Once again, someone who cared made an impression. I pulled myself togeth-er and graduated near the top of my class,” said Dr. DeVita.

Path to MedicineAfter earning his Bachelor of Sci-

ence degree in 1957, Dr. DeVita, fol-lowing his lifelong dream of becoming a doctor, enrolled in the George Wash-ington University School of Medicine

in Washington, DC. “When I entered George Washington, the university had just hired a new Chair of Physiol-ogy, C. Adrian Hogben. He assigned a paper on a scientific subject, and I de-cided to write about active transport, which was new at that time,” said Dr. DeVita, “I really didn’t think I did well, but Dr. Hogben gave me an A-plus and

asked if I’d like to do research with him over the summer at the Mount Desert Island Biological Laboratory in Bar Harbor, Maine. I hesitated, but he made me an offer I couldn’t refuse. He hired my wife as his secretary, so off we went to Maine.”

The summer research position proved instrumental in Dr. DeVita’s ca-reer path. “At the lab, I met Dr. David Rall who was Chief of Chemical Phar-

macology (that’s what it was called at the time) at the National Cancer In-stitute [NCI]. I’d really aced pharma-cology in medical school. I almost hit a perfect score on my national boards, and Dr. Rall was so impressed that he invited me to the National Institutes of Health [NIH] as a clinical associate. Frankly, I wasn’t sure what the NIH was, but the Vietnam War was raging and NIH service was equal to military service, so I decided to go to the NIH instead of the jungles in Vietnam,” said Dr. DeVita.

From Cardiology to OncologyDr. DeVita explained that in the

1960s, oncology was a field on the outskirts of medicine; cancer posed a daunting clinical conundrum that few were willing to tackle. Instead, cardiology was the center of gravity in medicine; implantable mechanical devices, heart transplants, and super-star surgeons like Michael DeBakey and Christiaan Barnard were the buzz.

Dr. DeVita began his career as a cardiology resident, doing cath-eterizations and writing papers; one, in fact, was heavily cited in the literature for more than a decade. However, he was still drawn to phar-

Combination drug therapy at that time was considered bad medicine. We had a hard time convincing the

oncology community that combination chemotherapy was a reasonable treatment. Even after we reported the

very impressive results from the first study, physicians wouldn’t use the regimen the right way.

— Vincent T. DeVita, Jr, MD


If she has ovarian cancer

TEST FOR BRCA

If indicated*

TREAT WITH LYNPARZA

Please see the following pages for additional Safety Information

and Brief Summary of the full Prescribing Information.

INDICATION

LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verifi cation and

description of clinical benefi t in confi rmatory trials.

SELECT SAFETY INFORMATION

Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confi rmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confi rmed, discontinue LYNPARZA.

*

Help her continue the fi ght withthe fi rst approved PARP inhibitor1

Trim: 10.5 x 14

If she has ovarian cancer

TEST FOR BRCA

If indicated*

TREAT WITH LYNPARZA

Please see the following pages for additional Safety Information

and Brief Summary of the full Prescribing Information.

INDICATION

LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verifi cation and

description of clinical benefi t in confi rmatory trials.

SELECT SAFETY INFORMATION

Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confi rmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confi rmed, discontinue LYNPARZA.

*

Help her continue the fi ght withthe fi rst approved PARP inhibitor1

Trim: 10.5 x 14

http://www.lynparza.com/?source=OLAC30380&utm_source=google&utm_medium=paid%20search&utm_term=lynparza&utm_content=Approval&utm_campaign=2015%20Lynparza%20Branded

LYNPARZA demonstrated an objective response

rate of 34% in patients with BRCA-mutated

advanced ovarian cancer who had been treated

with 3 or more lines of chemotherapy1

The effi cacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or

suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients

with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of

chemotherapy were enrolled. Effi cacy was based on objective response rate and duration of response.1

Objective response rate was defi ned as a ≥30% reduction in target lesion size, according to

RECIST criteria, as measured by CT or MRI and confi rmed at least 4 weeks later.2

• The rate of partial response was 32% and the rate of complete response was 2%1

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

0 2010 30

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

34%

OBJECTIVE RESPONSE RATE(95% CI: 26, 42)

MEDIAN DURATION OF RESPONSE7.9MONTHS

(95% CI: 5.6, 9.6)

Trim: 10.5 x 14

Warnings and Precautions

Myelodysplastic syndrome/Acute Myeloid Leukemia

Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confi rmed in 6 out

of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with

deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a

randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with

advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of

2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases)

were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary

MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous

chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA

until patients have recovered from hematological toxicity caused by previous chemotherapy

(≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood

counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks,

refer the patient to a hematologist for further investigations, including bone marrow analysis and

blood sample for cytogenetics. If MDS/AML is confi rmed, discontinue LYNPARZA.

Pneumonitis

Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients

present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a

radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation.

If pneumonitis is confi rmed, discontinue LYNPARZA.

Embryo-Fetal Toxicity

LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of

action and fi ndings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at

exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the

patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA.

If contraceptive methods are being considered, use effective contraception during treatment and

for at least one month after receiving the last dose of LYNPARZA.

Use in Nursing Mothers Nursing Mothers

It is not known whether olaparib is excreted in human milk. Because many drugs are excreted

in human milk and because of the potential for serious adverse reactions in nursing infants from

olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug,

taking into account the importance of the drug to the mother.

Trim: 10.5 x 14

LYNPARZA demonstrated an objective response

rate of 34% in patients with BRCA-mutated

advanced ovarian cancer who had been treated

with 3 or more lines of chemotherapy1

The effi cacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or

suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients

with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of

chemotherapy were enrolled. Effi cacy was based on objective response rate and duration of response.1

Objective response rate was defi ned as a ≥30% reduction in target lesion size, according to

RECIST criteria, as measured by CT or MRI and confi rmed at least 4 weeks later.2

• The rate of partial response was 32% and the rate of complete response was 2%1

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

0 2010 30

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

34%

OBJECTIVE RESPONSE RATE(95% CI: 26, 42)

MEDIAN DURATION OF RESPONSE7.9MONTHS

(95% CI: 5.6, 9.6)

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Warnings and Precautions

Myelodysplastic syndrome/Acute Myeloid Leukemia

Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confi rmed in 6 out

of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with

deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a

randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with

advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of

2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases)

were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary

MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous

chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA

until patients have recovered from hematological toxicity caused by previous chemotherapy

(≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood

counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks,

refer the patient to a hematologist for further investigations, including bone marrow analysis and

blood sample for cytogenetics. If MDS/AML is confi rmed, discontinue LYNPARZA.

Pneumonitis

Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients

present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a

radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation.

If pneumonitis is confi rmed, discontinue LYNPARZA.

Embryo-Fetal Toxicity

LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of

action and fi ndings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at

exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the

patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA.

If contraceptive methods are being considered, use effective contraception during treatment and

for at least one month after receiving the last dose of LYNPARZA.

Use in Nursing Mothers Nursing Mothers

It is not known whether olaparib is excreted in human milk. Because many drugs are excreted

in human milk and because of the potential for serious adverse reactions in nursing infants from

olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug,

taking into account the importance of the drug to the mother.

Trim: 10.5 x 14

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated

advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Please see accompanying Brief Summary of Full Prescribing Information.

LYNPARZA is a trademark of the AstraZeneca group of companies.©2015 AstraZeneca. All rights reserved. 3118712 Last Updated 4/15

References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

BLOOD AND LYMPHATIC DISORDERS

GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

INFECTIONS AND INFESTATIONS

MUSCULOSKELETAL AND CONNECTIVE

TISSUE DISORDERS

Anemia 34 18

Decreased appetite 22 1

Nausea 64 3

Vomiting 43 4

Diarrhea 31 1

Dyspepsia 25 0

Abdominal pain/discomfort 43 8

Fatigue/asthenia

Nasopharyngitis/URI

66 8

26 0

Arthralgia/musculoskeletal pain 21 0

Myalgia 22 0

CTCAE GRADES 1-4 (%) CTCAE GRADES 3-4 (%)

LYNPARZA 400 MG TWICE DAILY n=223Adverse Reactions Reported

in ≥20% of Patients1

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The safety and tolerability of LYNPARZA were also evaluated

in a randomized, placebo-controlled study1

• LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled

clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received

2 or more lines of platinum-containing chemotherapy1

• Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical

trials, with the addition of back pain, headache, cough, rash, and dysgeusia1

aPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

To learn more, including how to order LYNPARZA,

please visit www.lynparza.com

Decrease in absolute neutrophil count (neutropenia) 25 7

Decrease in platelets (thrombocytopenia) 30 3

Decrease in lymphocytes (lymphopenia) 56 17

Mean corpuscular volume elevation 57 -

Increase in creatininea 30 2

Decrease in hemoglobin (anemia) 90 15

LYNPARZA 400 MG TWICE DAILY

n=223


Laboratory Abnormalities1

Trim: 10.5 x 14

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated

advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Please see accompanying Brief Summary of Full Prescribing Information.

LYNPARZA is a trademark of the AstraZeneca group of companies.©2015 AstraZeneca. All rights reserved. 3118712 Last Updated 4/15

References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

BLOOD AND LYMPHATIC DISORDERS

GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

INFECTIONS AND INFESTATIONS

MUSCULOSKELETAL AND CONNECTIVE

TISSUE DISORDERS

Anemia 34 18


Nausea 64 3

Vomiting 43 4

Diarrhea 31 1

Dyspepsia 25 0


Fatigue/asthenia

Nasopharyngitis/URI

66 8

26 0


Myalgia 22 0


LYNPARZA 400 MG TWICE DAILY n=223Adverse Reactions Reported

in ≥20% of Patients1

Trim: 10.5 x 14

The safety and tolerability of LYNPARZA were also evaluated

in a randomized, placebo-controlled study1

• LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled

clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received

2 or more lines of platinum-containing chemotherapy1

• Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical

trials, with the addition of back pain, headache, cough, rash, and dysgeusia1

aPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

To learn more, including how to order LYNPARZA,

please visit www.lynparza.com

Decrease in absolute neutrophil count (neutropenia) 25 7




Increase in creatininea 30 2


LYNPARZA 400 MG TWICE DAILY

n=223


Laboratory Abnormalities1

Trim: 10.5 x 14


macology and asked Dr. Rall if he could work in the laboratory on the heart drug digoxin. “The chief, be-ing a wise person, said, ‘Sure, work on anything you like,’ and suddenly I was surrounded by these wildly

enthusiastic people doing cancer research,” Dr. DeVita said. “But that lasted about 2 weeks, because the challenge of oncology hooked me, and that’s essentially how I chose my career path,” said Dr. DeVita.

After returning from his residency stint at Yale, Dr. DeVita became Chief

of the Solid Tumor Service at NCI. “I didn’t have any senior faculty so I recruited George Canellos and Bob Young. Then Bruce Chabner joined us, and not long after that I reached out and got Phil Schein to sign up. We became known as ‘The Gang of Five.’ We were all around the same age, give

or take a few years. It was an intense relationship. We used to meet in the solarium on the 12th floor, pushing a blackboard on wheels. We’d write out protocols for studies, and it got pretty vocal at times, so much so that the trainees actually thought we were mad at each other. By the time

Vincent T. DeVita, Jr, MDcontinued from page 16

LYNPARZA™ (olaparib) capsules, for oral use

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGETreatment of gBRCA-mutated advanced ovarian cancerLynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATIONPatient SelectionSelect patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.Recommended DosingThe recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information].Dose Adjustments for Adverse ReactionsTo manage adverse reactions, consider dose interruption of treatment or dose reduction.The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.Dose Modifications for Use with CYP3A InhibitorsAvoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information].

CONTRAINDICATIONSNone

WARNINGS AND PRECAUTIONSMyelodysplastic syndrome/Acute Myeloid LeukemiaMyelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (�CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.PneumonitisPneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.Embryo-Fetal ToxicityLynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information].Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information].

ADVERSE REACTIONSThe following adverse reactions are discussed elsewhere in the labeling:• Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions

(5.1) in the full Prescribing Information]• Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in �20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

Table 1 Adverse Reactions Reported in �20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

3 or more lines of prior chemotherapy

Adverse Reaction Grades 1-4 Grades 3-4 N=223 N=223 % % Blood and Lymphatic disorders

Anemia 34 18

Gastrointestinal disorders



Nausea 64 3

Vomiting 43 4

Diarrhea 31 1

Dyspepsia 25 0

General disorders

Fatigue/asthenia 66 8

Infections and infestations

Nasopharyngitis/URI 26 0

Musculoskeletal and Connective Tissue disorders


Myalgia 22 0

Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.

Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

Laboratory Parameter* 3 or more lines of prior chemotherapy

Grades 1-4 Grades 3-4 N=223 N=223 % %


Decrease in absolute neutrophil count 25 7 (neutropenia)




Increase in creatinine* 30 2* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in �10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in �1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.Table 3 presents adverse reactions reported in �20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA- mutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

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LYNPARZATM (olaparib) capsules 2

Table 3 Adverse Reactions Reported in �20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0

Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 - 44 - Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONSOlaparib is primarily metabolized by CYP3A.Anticancer AgentsClinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.Drugs that may Increase Olaparib Plasma ConcentrationsIn patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information].Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Adminis-tration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].Drugs that may Decrease Olaparib Plasma ConcentrationsIn patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information].USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summaryLynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.Animal DataIn a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.Nursing MothersIt is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric UseThe safety and efficacy of Lynparza has not been established in pediatric patients.Geriatric UseIn clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged �65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE �3 which were reported more frequently in patients aged �65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.Females of Reproductive PotentialLynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their health-care provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.Hepatic ImpairmentThe effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT �2.5 X ULN (�5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information].Renal ImpairmentBased on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information].OVERDOSAGEThere is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.17 PATIENT COUNSELING INFORMATIONSEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE)• Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and

Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.

• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information].

• Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information].

• Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information].

• Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 198503079901 12/14 Issued: 12/2014

Trim: 7.625 x 10.5


we’d hashed out a protocol, it usu-ally ended up being pretty good. We stayed together for about 6 years; we started lymphoma programs, ovarian cancer programs, and breast cancer programs, things that are still making a difference today. To this day, they re-main friends of mine.”

Combination ChemotherapyIt was during this fecund period of

research at the NIH when Dr. DeVita would take his place in history, doing research in combination chemotherapy. Although this was a barrier-breaking concept, it was met with huge skepti-cism. “Everybody thought we were to-

tally off base,” Dr. DeVita said. “Com-bination drug therapy at that time was considered bad medicine. We had a hard time convincing the oncology commu-nity that combination chemotherapy was a reasonable treatment. Even after we reported the very impressive results from the first study, physicians wouldn’t

use the regimen the right way.”Despite the negativity, Dr. DeVita

and his colleagues developed practice-changing regimens: the CMF (cy-clophosphamide, methotrexate, and fluorouracil) regimen in breast cancer and the four-drug MOPP (mechlor-ethamine, vincristine, procarbazine [Matulane], and prednisone) regimen, which became the curative treatment for Hodgkin lymphoma. “To this day,” he said, “the( MOPP paper is the most

cited article in the history of the Annals of Internal Medicine.”

Asked if MOPP was the highlight of his career, Dr. DeVita said, “There have been many highlights, but seeing peo-ple who are 40 years out after a diagno-sis that prior to MOPP was essentially fatal is certainly at the top of the list.”

An Illustrious CareerIn 1980, President Jimmy Carter

appointed Dr. DeVita as Director of the NCI, a position he held until 1988. He was the first director to set cancer mortality goals for the nation. “There’s always been a gap between what is theoretically attainable and what can actually be accomplished in a country as large and diverse as ours. The govern-ment has a problem of setting up pro-grams without having the tools in place to measure the results. So I gathered about 300 consultants, and we set some measurable mortality goals for the year 2000. At the time, statisticians project-ed cancer mortality would increase in

NAME: Vincent T. DeVita, Jr, MD

TITLE: Amy and Joseph Perella Professor of Medicine and Professor of Epidemiology and of Public Health, Yale School of Medicine

MEDICAL DEGREE: MD, George Washington University School of Medicine

NOTABLE HONORS: Lasker-Debakey Clinical Medical Research Award (1972); the American Association for Cancer Research (AACR) Richard and Hinda Rosenthal Memorial Award (1986); the Pezcoller Foundation–AACR International Award for Cancer Research (1988); the Armand Hammer Prize for Cancer Research (1990); and the FREDDIE International Health & Medical Media Award (2007)


LYNPARZA™ (olaparib) capsules, for oral use

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGETreatment of gBRCA-mutated advanced ovarian cancerLynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATIONPatient SelectionSelect patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.Recommended DosingThe recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information].Dose Adjustments for Adverse ReactionsTo manage adverse reactions, consider dose interruption of treatment or dose reduction.The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.Dose Modifications for Use with CYP3A InhibitorsAvoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information].

CONTRAINDICATIONSNone

WARNINGS AND PRECAUTIONSMyelodysplastic syndrome/Acute Myeloid LeukemiaMyelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (�CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.PneumonitisPneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.Embryo-Fetal ToxicityLynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information].Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information].

ADVERSE REACTIONSThe following adverse reactions are discussed elsewhere in the labeling:• Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions

(5.1) in the full Prescribing Information]• Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in �20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

Table 1 Adverse Reactions Reported in �20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

3 or more lines of prior chemotherapy

Adverse Reaction Grades 1-4 Grades 3-4 N=223 N=223 % % Blood and Lymphatic disorders

Anemia 34 18

Gastrointestinal disorders



Nausea 64 3

Vomiting 43 4

Diarrhea 31 1

Dyspepsia 25 0

General disorders

Fatigue/asthenia 66 8

Infections and infestations

Nasopharyngitis/URI 26 0

Musculoskeletal and Connective Tissue disorders


Myalgia 22 0

Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.

Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

Laboratory Parameter* 3 or more lines of prior chemotherapy

Grades 1-4 Grades 3-4 N=223 N=223 % %


Decrease in absolute neutrophil count 25 7 (neutropenia)




Increase in creatinine* 30 2* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in �10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in �1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.Table 3 presents adverse reactions reported in �20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA- mutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

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LYNPARZATM (olaparib) capsules 2

Table 3 Adverse Reactions Reported in �20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0

Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 - 44 - Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONSOlaparib is primarily metabolized by CYP3A.Anticancer AgentsClinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.Drugs that may Increase Olaparib Plasma ConcentrationsIn patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information].Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Adminis-tration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].Drugs that may Decrease Olaparib Plasma ConcentrationsIn patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information].USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summaryLynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.Animal DataIn a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.Nursing MothersIt is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric UseThe safety and efficacy of Lynparza has not been established in pediatric patients.Geriatric UseIn clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged �65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE �3 which were reported more frequently in patients aged �65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.Females of Reproductive PotentialLynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their health-care provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.Hepatic ImpairmentThe effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT �2.5 X ULN (�5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information].Renal ImpairmentBased on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information].OVERDOSAGEThere is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.17 PATIENT COUNSELING INFORMATIONSEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE)• Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and

Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.

• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information].

• Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information].

• Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information].

• Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 198503079901 12/14 Issued: 12/2014

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a linear fashion, when in fact mortality did drop, and more than expected.”

Dr. DeVita left the NCI in 1988 and served as Physician-in-Chief and At-tending Physician at Memorial Sloan Kettering Cancer Center until 1993. From there, he became Director of the Yale Cancer Center, a position he held from 1993 to 2003. Dr. DeVita is still with Yale University, serving as the Amy and Joseph Perella Professor of Medicine and Professor of Epidemiol-

Vincent T. DeVita, Jr, MDcontinued from page 23

ogy and of Public Health.Dr. DeVita recently wrote a book

about the war on cancer for the lay public, called The Death of Cancer. His daughter, Elizabeth DeVita-Raeburn, a science writer, worked on it with him. Dr. DeVita said, “Elizabeth keeps me honest about communicating on a hu-man level with nonmedical people.”

Over the course of his illustrious career, Dr. DeVita has received numer-ous awards including the Lasker–De-bakey Clinical Medical Research Award (1972), the American Association for

Cancer Research (AACR)–Richard and Hinda Rosenthal Memorial Award (1986), the Pezcoller Foundation–AACR International Award for Cancer Research (1988), the Armand Hammer Prize for Cancer Research (1990), and the FREDDIE International Health & Medical Media Award (2007).

Dr. DeVita is the author or coau-thor of more than 450 scientific ar-ticles. Most notably, he is one of the three editors of Cancer: Principles & Practice of Oncology, the premier text-book in the oncology field. The text-

book, first published in 1982, is now in its 10th edition.

Dr. DeVita said he remains firmly “an optimist” in the war on cancer, despite some qualms about what he considers a movement toward government-driven paradigms that may stifle innovation. He used achievements in breast cancer ther-apy as an example of where optimism can lead. “Years ago, women with all stag-es of breast cancer had radical mastecto-mies, leaving just tissue over bone and a painful swollen arm. Then they died,” he said. “Look how far we’ve come.” n

Sandra J. Horning, MD

D ue to childhood health issues, Sandra J. Horning, MD, formed

an opinion about doctors at a young age: They were good people who helped other people. By her early teens, Dr. Horning began to ponder a career in medicine, which offered the possibil-ity of blending her love of science with a career that would benefit the lives of others. “I grew up in a small town in Iowa called Creston, and physicians were among the most respected citizens in our community. But I also found it in-teresting that when I went to the clinic, all of the nurses were women and the doctors were men. As a young girl, I wondered why that was so,” Dr. Horn-ing told The ASCO Post.

Dr. Horning had no family mem-bers close or distant who worked in the medical field, so it was purely experien-tial knowledge that drew her into medi-

Lymphoma Expert and Industry Leader Sandra J. Horning, MD, Pushes the Frontiers of Drug Development and Oncology Research

cine. “I was the first on either side of my family to go to medical school. I think I was 14 years old when I firmly decided that I was going to be a doctor. I was an early feminist, so wanting to break into what I perceived as a male-dominated profession probably added to my desire to become a doctor,” said Dr. Horning.

She continued, “I went to the Uni-versity of Iowa, and my goal in college was to learn as much about everything as possible in the humanities and other areas in the liberal arts, because I real-ized that once I entered medical school my studies would be narrowed to med-icine. Although I was a serious student, I had a great time at college and par-ticipated in a lot of campus activities, including a sorority.”

Early Medical CareerDr. Horning graduated from college

in 3 years, earning her BA in 1971, and then worked for a year in a laboratory. “During the second half of that period in the lab, my father was diagnosed with advanced metastatic cancer. It was the first bad thing that had ever really hap-pened in my life. Even though I wanted to be a doctor, up until then I had no

experience with desperately ill people, certainly not people who were dying of a disease. My father lasted for about 6 months, which took me into the third week of medical school. It was a very important event in my life, because it altered my financial situation and made me grow up and mature very quickly. It also solidified my passion to make a dif-ference in the world,” said Dr. Horning.

She continued on at the Univer-sity of Iowa, entering the university’s

medical school, where she received her MD degree in 1975. “Early on in medi-cal school I had decided to do internal medicine, which I found more cerebral and challenging than the other options. By then I felt I needed to move on from Iowa. It had been a great experience, but I wanted to broaden my horizons, so I

went to the University of Rochester in New York to do my internship and resi-dency,” said Dr. Horning.

“I had a wonderful peer group that I really enjoyed working with. Two of my colleagues from Stanford University were among the most brilliant people I’d ever met, and during our discussions they told me about exciting research that was going on there, particularly in the areas of immunology and lympho-ma research. It was also during a time

NAME: Sandra J. Horning, MD

TITLE: Executive Vice President, Global Development and Chief Medical Officer, Genentech

MEDICAL DEGREE: MD, University of Iowa

NOTABLE HONORS: Best Doctor in America (1992–2008); Alwin C. Rambar–James B. D. Mark Award for Excellence in Patient Care, Stanford University School of Medicine (2000); Fellow, American Society of Clinical Oncology (2007); Distinguished Alumnus Award, University of Iowa (2009); Fierce Biotech Top Women in Biotech Award (2014)

I’m extremely excited about how the convergence of science and technology is leading us to the next frontier

in cancer research and drug development. With these new possibilities comes a lot of responsibility, but the oncology community is ready to collaborate and lead

the way forward. —Sandra J. Horning, MD


when some important work was being done in cancer, such as in adjuvant ther-apy in breast cancer, as well as the first curative combination chemotherapies in lymphomas,” said Dr. Horning.

Several issues contributed to Dr. Horning’s next career move. “Having my father die of cancer combined with my overarching love of science and ded-ication to helping others made me want to be someplace that was on the cutting edge of research and discovery in the oncology field. So I decided to fulfill that dream and went to Stanford for my oncology fellowship,” said Dr. Horning. She completed her residency at Roch-ester University in 1978 and crossed the country, arriving at Stanford University School of Medicine later that year.

Asked if there were any mentors of note that helped shape her early career choices, Dr. Horning said, “Dr. John Bennett, who was ASCO’s 2011 recipi-ent of the B. J. Kennedy Award and Lec-ture for Scientific Excellence in Geriat-ric Oncology and also did seminal work in the characterization/classification of acute leukemia, mentored me at the University of Rochester. He was influ-ential in my career decisions and was very supportive along the way.”

Practice-Changing Clinical Research in Lymphoma

When Dr. Horning went to Stan-ford, it was at the time when monoclo-nal antibodies were first surfacing and hybridoma technology had just come to the forefront. There was a young inves-tigator at Stanford named Ronald Levy, MD, who was working in this area, and Dr. Horning’s hope was to join his labo-ratory after she’d done a year of clinical fellowship. “However, as I was doing my training, I realized that I really enjoyed clinical research, and two individuals, ASCO Past President Dr. Saul Rosen-berg and Dr. Henry Kaplan, enhanced that experience. I worked with them in the Hodgkin lymphoma clinic and was involved with patients on clinical trials.”

“During that time I became inter-

ested in the classification of lymphomas and the biology behind that work, so I decided to pursue a career in clinical investigation, working in conjunction with investigators in the laboratory,” said Dr. Horning. “Actually, my closer colleagues were in pathology, where we were doing some of the first work in lymphoma classification, understand-ing that lymphoma was a T-cell and B-cell lineage.”

Dr. Horning described her career arc at Stanford as multipronged. “My career at Stanford moved across par-allel veins. One was working closely with colleagues in pathology as we were seeking to better understand non-Hodgkin lymphoma. I was also able to leverage the Stanford Lym-phoma Database to examine the natu-ral history of indolent disease by ob-serving patients over a long period. I was involved in the process to charac-terize the lymphomas right up to my participation in the World Health Or-ganization classification of lymphoid neoplasms,” said Dr. Horning.

She continued, “Interventional clinical investigations comprised a large part of my academic career. Even-tually while working with the Eastern Cooperative Oncology Group, I was involved in two large trials, one in in-dolent non-Hodgkin lymphoma and the other in aggressive non-Hodgkin lymphoma, in which we integrated rituximab [Rituxan] into the standard of care. Both trials were registered as part of the package of information in a supplemental Biologics License Ap-plication for the U.S. Food and Drug Administration. What truly impressed me was how a single novel therapy changed the tenor of my clinic. Patients were being cured in unprecedented numbers, and disease progressions be-came fewer and farther between.”

From ASCO to IndustryDuring this period, Dr. Horning’s

work in Hodgkin and non-Hodgkin lymphoma also centered on quality-of-

life and survivorship issues, work that she carried into her ASCO presidency in 2006. “Being President of ASCO was certainly one of the highlights of my pro-fessional career. Long before I became President, ASCO was a big part of my academic life and career development. The Society is just a wonderful forum fostering collaboration on the national and international stages, and an added dimension that helps round out a career in oncology,” said Dr. Horning.

Dr. Horning commented that her presidency at ASCO helped hone her leadership and organizational skills. “The Society’s focus on poli-cy is something that has always ap-pealed to me because I believe that good policies can truly change the world. My presidency was focused on survivorship issues and the sci-ence behind the newly emerging targeted therapies. Under my presi-dency, there were also some orga-nizational changes that I believe set the Society up for future health and success. Foremost was the search for a CEO. My legacy will probably be in finding and hiring Dr. Allen Lich-ter for that position, because there is unanimous agreement that Allen has done a superb job taking ASCO to the next level, said Dr. Horning.

In 2009, Dr. Horning left her posi-tion as a tenured Professor of Oncol-ogy at Stanford University School of Medicine to enter the pharmaceutical industry, taking a leadership roll at Ge-nentech. She said that her ASCO presi-dency influenced her decision to leave academia, noting that being in a leader-ship position in ASCO’s big platform informed her own desire to to make progress in multiple cancer types, and on a global front.

“I joined Genentech as the Glob-al Head of Oncology/Hematology Clinical Development. During my tenure, we were fortunate in having five new drugs approved, which was very fulfilling. I also had the oppor-tunity to participate in some ground-

breaking developments, including Breakthrough Therapy Designation for drugs showing early promise of substantial benefit and pathologic complete response in early breast cancer as an endpoint for accelerated approval. I’ve really been impressed with the dynamic structure of the company and was thrilled when the opportunity arose that led to my cur-rent position as Chief Medical Of-ficer and Head of Global Product Development. So I went from having about 200 people in my organization to 4,000 personnel around the globe,” said Dr. Horning.

Dr. Horning has authored or coau-thored more than 300 peer-reviewed journal articles, book chapters, reviews, and editorials and has served on the ed-itorial boards of several peer-reviewed medical journals, including the Journal of Clinical Oncology, Clinical Cancer Re-search, Clinical Lymphoma, Leukemia & Lymphoma, the Annals of Internal Medicine, and the American Journal of Medicine. She has been named a “Best Doctor in America” consecutively from 1992 to 2008 and received the 2010 Top Women in Bay Area Business Award and the 2014 Fierce Biotech Top Women in Biotech Award.

How has a career spanning small-town beginnings in Iowa to the presi-dency of ASCO and on to a leadership position at one of the world’s premier drug companies shaped her view of oncology’s future? Dr. Horning re-plied, “Advances such as molecular se-quencing and cancer immunotherapy are changing the face of oncology. I’m extremely excited about how the con-vergence of science and technology is leading us to the next frontier in can-cer research and drug development. With these new possibilities comes a lot of responsibility, but the oncology community is ready to collaborate and lead the way forward.”

Disclosure: Dr. Horning is Chief Medical Officer and Head of Global Product Development for Genentech. n

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and Trinity College Dublin. In 1986, he was appointed Professor of Surgery and consultant urologist in the Mater Hospital and University College Dub-lin. He remained on as Professor and Chairman for 25 years at the Depart-ment of Surgery, Mater Hospital, and University College in Dublin.

Dr. Fitzpatrick served as Editor-in-Chief of BJU International from 2003 to 2012. He also served as President of the British Association of Urologi-cal Surgeons and the Irish Society of Urology. From January 2012 until his death, he was Head of Research for the Irish Cancer Society. ❧

Jesse L. Steinfeld, MDJanuary 6, 1927–August 5, 2014

In 1971, then Surgeon General Jesse L. Steinfeld, MD, took Big To-

bacco to task, stating, “Let me sug-gest that certain purveyors of ciga-rettes stop making remarks about how some young mothers in child-birth might welcome smaller babies. The mother who smokes is subject-ing the unborn child to the adverse effects of tobacco, and as a result we are losing babies and possibly handi-capping babies.”

Dr. Steinfeld earned his MD in 1949 from what is now called Case Western Reserve University. In 1954, Dr. Steinfeld took a position at the National Cancer Institute (NCI), serving as Director of the Radioiso-tope Laboratory until 1958. In 1959, he returned to California, where he joined the faculty of the University of Southern California School of Medi-cine, serving as Assistant Professor of Medicine, rising to Associate Profes-sor in 1963 and full professorship in 1967. Dr. Steinfeld returned to the NCI in 1968, serving as Associate Di-rector for Programs. Later that same year, he was appointed Deputy Assis-tant Secretary for Health and Scientif-ic Affairs, and on December 18, 1969, he became the U.S. Surgeon General.

During his tenure as Surgeon Gener-al, Dr. Steinfeld also served as ASCO’s seventh President, from 1970 to 1971.

Dr. Steinfeld’s antitobacco stance was bold and unequivocal, leading him to become Big Tobacco’s worst enemy. Remarkably, his two prede-cessors had been smokers. Dr. Stein-

feld removed all the ashtrays and placed no-smoking signs in his of-fices. Citing numerous studies show-ing that women were less likely than men to quit smoking, he spearhead-ed a campaign to reduce the number of female smokers. He also warned against the dangers of secondhand

smoke. Many of his ideas about ban-ning smoking on airplanes, trains, restaurants, the workplace, and other public places would take hold de-cades later, as antismoking activists lobbied for and achieved smoke-free zones. But at the time, they were considered radical.

Jesse L. Steinfeld, MD

In Memoriamcontinued from page 13

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Dr. Steinfeld resigned as Surgeon General in 1972. He then spent a year at the Mayo Clinic and 2 years at the Uni-versity of California, Irvine. From 1976 to 1983, Dr. Steinfeld served as Dean at the Medical College of Virginia School of Medicine. He became President of the Medical College of Georgia in 1983. ❧

Lee W. Wattenberg, MDDecember 21, 1921–December 9, 2014

One of the early giants in the field of cancer prevention, Lee W. Wat-tenberg, MD, published in 1966 what would be regarded as a land-mark paper in the American Associ-ation for Cancer Research (AACR)

journal Cancer Research. During his research, he reviewed 36 years of an-imal studies, looking at the effects of various compounds on carcinogen-esis, which set forth the framework for understanding how these com-pounds worked. It was in this semi-nal paper that Dr. Wattenberg intro-

duced the term “chemoprophylaxis.”Dr. Wattenberg contributed pro-

lifically to the scientific literature, constantly advancing the field of cancer prevention. He would later investigate two categories of chemo-preventive agents: synthetic com-



pounds that might prevent carcino-gen-induced lung cancer and dietary constituents, such as the cruciferous plants cabbage and broccoli.

He also studied the processes that cause irreversibility in carci-

nogenesis and sought to determine whether and how these processes could be targeted for intervention. Adding to his list of research accom-plishments, Dr. Wattenberg also pio-neered the use of aerosols to deliver drugs in lung cancer.

Dr. Wattenberg was President of

the AACR from 1992 to 1993 and was elected as a Fellow of the AACR Academy in 2013. His many con-tributions to the AACR included terms as Associate Editor for Cancer Research and Cancer Epidemiology, Biomarkers & Prevention. Dr. Wat-tenberg also served on the AACR

Board of Directors from 1985 to 1988 and from 1991 to 1994. Dur-ing his presidency, he launched the Associate Member Council in 1992 to represent the interests of early-career scientists.

In a tribute to Dr. Wattenberg, Margaret Foti, PhD, MD, Chief Ex-ecutive Officer of the AACR, noted, “About two-thirds of all cancers are preventable. Because of Lee Watten-berg’s dedication to and belief in the promise of cancer prevention, the field has taken its rightful place as one of the most important areas of cancer research.” ❧

Dorothy ‘Dottie’ Thomas September 18, 1922–January 9, 2015

Dorothy “Dottie” Thomas was wife and research partner to 1990 Nobel laureate E. Donnall Thomas, MD, pioneer of the bone marrow transplant and former Director of the Clinical Research Division at Fred Hutchinson Cancer Research Center. Dr. and Mrs. Thomas formed the core of a team that proved bone marrow transplantation could cure leukemias and other blood cancers, work that spanned several decades.

Mrs. Thomas was a journalism ma-jor in college when in March 1943, Don was admitted to Harvard Univer-sity Medical School under a U.S. Army program. “Dottie and I talked it over, and we decided that if we were going to spend time together, she probably ought to change her profession,” Don told The Seattle Times in a 1999 inter-view. “She’d taken a lot of science in her time in school.”



Dorothy ‘Dottie’ Thomas

Lee W. Wattenberg, MD


Alan F. List, MD

Nationally Recognized Leader in Myeloid Malignancies, Alan F. List, MD, Has High Hopes for the Future of Oncology

The Tampa Bay area of Florida is a haven for golfers and fishermen

looking to unwind under the warm tropical skies. And the clean highways stretching through the scenic west coast of Florida are also a perfect ex-cuse for weekend motorcycle enthu-siasts, such as Alan F. List, MD, the President and CEO of Moffitt Cancer Center, to hit the road. “My wife and I both have Harley-Davidson motor-cycles. I’d always wanted one and I was able to talk her into it, so about 8 years ago we bought a pair of Harleys, learned to ride, and now we go out to-gether on weekends. It’s a lot of fun,” Dr. List told The ASCO Post.

A Father’s InfluenceDr. List grew up in York, Penn-

sylvania, a Pennsylvania Dutch com-munity in the south-central region of the state, bordered by the Susque-hanna River, which is the longest river on the East Coast. “I grew up in a very Germanic heritage. York is a nice place. In fact, it’s where the Harley-Davidson motorcycle was first made,” said Dr. List.

When asked about any early influ-ences that might have affected his de-cision to pursue a career in medicine, Dr. List said without hesitation, “The one major influence on my decision to become a doctor and on my career was my father, who was a medic in

World War II. He always told me that being a physician is the most reward-ing thing that anyone could ever do, and he wanted me to consider medi-cine as a career. So, from the time I was a young boy, I had that thought lingering in the back of my head,” said Dr. List.

After high school, Dr. List entered Bucknell University, majoring in bi-ology. “I had the opportunity to take advantage of what Bucknell called the ‘January Plan,’ which is a 6- to 8-week internship program, and did volunteer work in a hospital. I just loved it. My father’s enthusiasm for medicine cou-pled with the real-world experience in the hospital sealed the deal in my mind, and I decided to become a doc-tor,” said Dr. List.

Dr. List’s father also had advice for his son’s specialty. “My father wanted me to become a surgeon, a specialty he would have chosen given his experiences in combat, but he never had a chance to pursue a medical career after the War. At the end of my first year in college, I was exposed to the research lab and I ended up getting both my bachelor’s and master’s degrees by the time I graduated Bucknell in 1976. During my 4 years in college, I’d developed the bug for research, which essen-tially set my career path in motion. I wanted to do medicine but to com-

NAME: Alan F. List, MD

TITLE: President and CEO, Moffitt Cancer Center; Senior Member, Department of Malignant Hematology and Experimental Therapeutics Program; Professor of Internal Medicine and Oncology, University of South Florida College of Medicine

MEDICAL DEGREE: MD, University of Pennsylvania

NOTABLE HONORS: General Motors Cancer Research Foundation-Merit Award for “Accomplishments in Leukemia Research” (1991); J. P McCarthy International Prize for Advancing the Body of Scientific Knowledge in Myelodysplastic Syndrome, J. P. McCarthy Foundation (2004); Emil J. Freireich Award for Clinical Research, MD Anderson (2005); The Joshua Lederberg Society (2009); Charter Fellow, National Academy of Inventors (2013)

bine it with clinical and laboratory research,” said Dr. List.

Captivated by OncologyDr. List continued, “In 1976, I en-

rolled in medical school at the University of Pennsylvania, which at the time had one of the best teaching curricula in the country. Although I’d had brief exposure to hematology and oncology during my years at Penn, it wasn’t a field that was on my radar screen at the time. I had a great experience at Penn, and after graduat-

ing, I headed west for my internship and residency in internal medicine at Good Samaritan Medical Center in Phoenix, Arizona,” said Dr. List.

It was during the early 1980s, around the time when clinicians and researchers were hoping that the mi-raculous activity of platinum drugs in testicular cancer would be a harbinger of a whole wave of active therapeutics. “It was a stimulating time when some of the most promising oncology re-search was being done, which was pro-ducing breakthroughs in cancer treat-ment. I was captivated by the progress and certainly wanted to be part of it,” said Dr. List.

Like many young doctors who have gone into the field of oncology, Dr. List was impressed by the resiliency and will of cancer patients. “I remem-ber working on the oncology floor of the hospital and being truly inspired by the patients. Here you have people who are staring at their own mortality

and yet they were so gracious for any help we could give them,” said Dr. List

Passion for HematologyIt was toward the end of his residen-

cy when Dr. List’s passion for hematol-ogy bloomed. “There was an attending physician at Arizona whom I was privi-leged to work with and learn from, Dr. Phil Scheerer, who was Phoenix’s first hematologist. What I loved about he-matology—the way I was trained—was that you read your own bone

marrows. So not only do you assess the patient and deal with the clinical issues, but as a hematologist you could serve as your own pathologist, catego-rizing and treating the disease, which gives you incredible insight into the bi-ology of the disease,” said Dr. List.

About his early mentor, Dr. List commented, “Dr. Scheerer was an ex-cellent bone marrow diagnostician and was not only a great clinician and car-ing with patients, but was also highly respected among all the oncologists and the few hematologists in the state.”

He continued, “As a researcher in-volved in myeloid malignancies, an-other intriguing characteristic of he-matology was that you could actually access and study the disease through a bone marrow aspirate, which, in large part, was the aspect of hematology that eventually sold me on the field. After my residency program, I went to Vanderbilt University Medical Cen-

After immunology, the next big game changer is going to be systems biology, integrating all these events at a

convergence point that can be exploited therapeutically. We are at a period of tremendous opportunity in oncology

and I’m very optimistic about the future. —Alan F. List, MD



ter in Nashville, Tennessee, to do a fellowship in hematology; the hema-tology and oncology programs were separate. As a hematology fellow, you read all the bone marrows with the attendings and spent a year reading out lymphomas, which at that time was with Dr. Bob Collins,” said Dr. List. “During my time at Vanderbilt, I became comfortable with pathology and trusted only my own interpreta-tion, which would prove invaluable to my work in the research lab.”

Groundbreaking Research in Myelodysplastic Syndromes

After completing his fellowship, Dr. List joined the faculty at the Uni-versity of Arizona. “When I arrived at the university, the diseases that weren’t covered by a program were myelodys-plastic syndromes and acute myeloid leukemia (AML). And I felt they were terrific challenges, particularly myelo-dysplastic syndromes, so that’s the area I concentrated on,” said Dr. List.

Dr. List’s early research interest in AML focused on multidrug resistance. “We tested cyclosporine as a potential inhibitor of P-glycoprotein in the labora-

tory and then in a phase I/II study and took it to a phase III trial in Southwest Oncology Group, which to this day is the only phase III study in high-risk AML to show a survival benefit,” noted Dr. List.

Following the success with AML, Dr. List focused on myelodysplastic syndromes, which occupied much of his research efforts over the past 15 or so years. His curiosity eventually led his studies into the potential of antiangiogenic therapies in myeloid malignancies. “Angiogenesis inhibi-tors were first found to be important in solid tumors, but we were able to show that the blasts in myelodysplas-tic syndromes and AML not only ex-press and secrete vascular endothelial growth factor (VEGF), but they also have receptors for VEGFR-1 and -2,” said Dr. List.

He explained that the early work led to the screening of several antian-giogenic agents, including some im-munomodulatory drugs they received from Celgene Corporation. “We found that one drug was particularly effective in enhancing erythropoiesis in myelo-dysplastic syndromes, which was le-nalidomide [Revlimid]. We took it to a phase I/II trial that led to the discovery of its activity in del(5q), and within 3

years, we completed a multicenter trial that led to the registration and U.S. Food and Drug Administration ap-proval of lenalidomide in myelodys-plastic syndromes,” said Dr. List.

Taking the Reins at MoffittAsked how a passionate research

physician stepped out of the lab to become the President and CEO of a comprehensive cancer center, Dr. List responded, “I realized that to advance the field you need coordinated teams. I was very happy at the University of Arizona; however, when I visited Moffitt, I realized the uniqueness of its structure. All the departments are team- and disease-based on the clinical side regardless of your discipline, and I saw the opportunity for much broader collaborative work than I had at Arizo-na. So I came to Moffitt in 2003 as the Program Head of Malignant Hematol-ogy, and in 2008, I assumed the role of Physician-in-Chief, overseeing all the clinical science activities. And in 2011, I was proud to become the President and CEO of Moffitt.”

Asked how Moffitt is positioned in the current fiscal challenges of today’s health-care environment, Dr. List said, “We’re the third largest cancer center

in the country, but we’re a young insti-tution so we haven’t had time to build the philanthropic base and founda-tion support that older institutions do. Having said that, we’re doing well; in fact, for the past several years, we’ve been well ahead of budget. We’ve also focused on sponsored research agree-ments with pharmaceutical compa-nies, which has helped us fund impor-tant research in a challenging funding climate at the National Institutes of Health. It’s been a healthy and creative partnership,” said Dr. List.

The launching pad for Dr. List’s ca-reer was in the hyperproductive 1980s, a true frontier land in oncology, when science, discovery, and drug develop-ment happened at breakneck pace. Retaining much of that original enthu-siasm, Dr. List has high hopes for the potential of immunotherapy, but he feels the next paradigm change will oc-cur in the intersection of science and technology. “After immunology, the next big game changer is going to be systems biology, integrating all these events at a convergence point that can be exploited therapeutically. We are at a period of tremendous opportunity in oncology, and I’m very optimistic about the future,” said Dr. List. n

Alan F. List, MDcontinued from page 29

John L. Marshall, MD

John L. Marshall, MD, a global leader in the research and treat-

ment of gastrointestinal cancers, grew up in Lexington, Kentucky, in a family that put high value on education. As a young boy, science was already on his mind; he enjoyed the explorative nature that chemistry and biology of-fered. However, his introduction to oncology came too soon. “When I was kid, my mother developed non-Hodg-kin lymphoma. After school I’d go with her to the clinic, where I witnessed ra-diation and chemotherapy and the ter-rors associated with many of the treat-ments in those days. She ultimately

Global Leader in Drug Development John L. Marshall, MD, Calls for a Smarter War on Cancer

died after about a 7-year battle with the disease,” said Dr. Marshall.

“I was nearly 14 when my mother died. That’s a tough age, a time of transformation when you struggle be-tween being a kid and an adult. After that kind of trauma, a kid can lose him-self in anger or charge ahead. I chose to charge ahead and become a doctor,” said Dr. Marshall.

Relishing the Role of an Outsider

It was a time when M*A*S*H was the most popular show on TV. Off-beat martini-drinking surgeons of the

returned to his home state, entering the University of Louisville School of Medicine; he received his MD degree in 1988.

“One good thing about going to school in Kentucky is that you’re al-most certain to have at least one team in the NCAA final four. That perk aside, I left Kentucky and did my internship at Georgetown University Medical Cen-ter, completing that in 1989 and stay-ing at Georgetown for my residency in internal medicine,” said Dr. Marshall.

“I loved the atmosphere at Georgetown, so after my internship,

4077th Mobile Army Surgical Hospi-tal cared for the wounded during the Korean War. “I was always the cutup in class, so I identified with the char-acter ‘Hawkeye’ in M*A*S*H. That’s who I modeled myself after: a good doc with an irreverent, mischievous personality. I still bring those qualities to my lectures and into the clinic,” said Dr. Marshall.

Dr. Marshall left Kentucky and went to a boarding school in Wash-ington, DC. After graduating board-ing school, Dr. Marshall went to Duke University, where he obtained a BS degree in psychology in 1982. He then continued on page 32

EVERY ADVANCE MATTERS

* Worldwide prevalence of squamous NSCLC based on World Health Organization/GLOBOCAN estimates of worldwide lung cancer prevalence and distribution of histology as reported by the American Cancer Society.

In 2012, there were an estimated 450,000 cases of squamous NSCLC worldwide.*2,3 Unfortunately, despite decades of research, the median overall survival for squamous NSCLC remains at approximately 8 to 10 months.4,5

Lilly Oncology is committed to finding treatment advances for people living with lung cancer.

VISIT SQUAMOUSNSCLC.COM TO LEARN MORE.

MANY PEOPLE DIAGNOSED WITH SQUAMOUS NSCLC:

STILL WAITINGFOR NEW TREATMENT OPTIONS TO EVOLVE1

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

MARCH 2015 GLOONC00009a


JOB#: 30725 ARTIST:



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EVERY ADVANCE MATTERS

* Worldwide prevalence of squamous NSCLC based on World Health Organization/GLOBOCAN estimates of worldwide lung cancer prevalence and distribution of histology as reported by the American Cancer Society.

In 2012, there were an estimated 450,000 cases of squamous NSCLC worldwide.*2,3 Unfortunately, despite decades of research, the median overall survival for squamous NSCLC remains at approximately 8 to 10 months.4,5

Lilly Oncology is committed to finding treatment advances for people living with lung cancer.

VISIT SQUAMOUSNSCLC.COM TO LEARN MORE.

MANY PEOPLE DIAGNOSED WITH SQUAMOUS NSCLC:

STILL WAITINGFOR NEW TREATMENT OPTIONS TO EVOLVE1

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

MARCH 2015 GLOONC00009a


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http://www.lillyoncology.com

http://www.medscape.com/infosite/172365.1/public


we do is peer-reviewed, and it is a sys-tem that totally embraces the current mainstream thought and looks sus-piciously at those who may come at a cancer problem from a different angle. Inadvertently, the current system has a way of stifling innovation.”

“We were a small group back then holding up the flame of immuno-therapy all the while battling a bar-rage of negativity. That’s why we are overjoyed that immunotherapy is finally getting the attention it de-serves,” he commented.

According to Dr. Marshall, the breaking point for mainstream ac-ceptance of immunotherapy was dis-covering checkpoint inhibitors. “I think that we’ve finally convinced the skeptics. The growing understanding of the science behind immunotherapy is generating increased interest from the clinical community, and as we get more encouraging results from on-going studies, I think we will see the ‘bandwagon’ grow,” said Dr. Marshall.

A Smarter War on CancerAlthough an avowed optimist, Dr.

Marshall noted a huge disconnect be-tween patients, the cost of care, and the clinical benefit of cancer treat-ment. He stressed that cancer medi-cine is publicly regarded as an area of significant progress, adding many new therapies to the market. How-ever, he added a sobering reminder. “Since 1971, when Richard Nixon declared war on cancer, we’ve spent

countless billions of dollars on re-search, yet we have made only rela-tively minor progress.”

Dr. Marshall said that in some ways we are collectively waving the white flag and have given up on the idea of trying to win the war on cancer. For example, he cited that few cancer clinical trials are designed to “cure” patients; instead they are aimed at detecting small differences between the treatments being compared. “The

I decided to stay. I’m currently Chief of the university’s Hematology/Oncology Division. My focus is on new drug development. I’ve joked in the past that I grew up in the 1970s, so I’ve been testing new drugs for a long time, and now I’m choosing to test them on others,” said Dr. Mar-shall with a laugh.

Dr. Marshall stressed that although much of his energy is focused on devel-oping new therapeutics, unlike many researchers, he does not favor the large randomized trial setting. “I’ve not been a major contributor to the cooperative group structure. Simply put, I’ve always thought that bigger trials yield smaller benefits. And in cancer, we have so far to go that I feel we should be spending our time, energy, and money on more dramatic pathways to discovery,” said Dr. Marshall.

Immunotherapy’s Renaissance “My longtime subspecialty, if you

will, has been in immunotherapy,” said Dr. Marshall. “I pride myself in being one of the few clinicians who explored immunotherapy when it was not taken seriously by the main body of oncol-ogy. I remember very distinctly being regarded as somewhat crazy for hav-ing such passion over immunetherapy. Other less critical people called me overidealistic for believing in immu-notherapy’s potential.”

Due to the embedded pessimism

within oncology circles about im-munotherapy’s promise, Dr. Marshall struggled for more than 20 years with grant applications and rallying sup-port and backing for clinical trials. Asked why he and other like-minded researchers faced such opposition, Dr. Marshall replied, “I recently read The Emperor of All Maladies, and it’s clear that in cancer we get ideas about which is the right path to take and we don’t like to deviate. Remember, everything

John L. Marshall, MDcontinued from page 30

NAME: John L. Marshall, MD

TITLE: Chief, Division of Hematology/Oncology, MedStar Georgetown University Hospital; Chief, Division of Hematology/Oncology, Georgetown University Hospital; Associate Director, Clinical Research, Lombardi Comprehensive Cancer Center; Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers

MEDICAL DEGREE: MD, University of Louisville School of Medicine

NOTABLE HONORS: America’s Top Doctors for Cancer (2008–2014); Celebration of Hope Award (shared with his wife, Liza; 2009)

oncology research and treatment com-munity should ask itself a simple ques-tion: Can we do something different to move the outcomes needle forward?” said Dr. Marshall.

“When we talk about giving pa-tients standard of care we know that it is not going to dramatically improve our outcomes. And I’ve always won-dered why our patients haven’t been more aggressive in their own advocacy. There seems to be too much patient acceptance, by both doctors and pa-tients,” said Dr. Marshall. Could he of-fer a reason for this decades-long pas-sivity? “Well, the short answer is that cancer patients are scared for their lives and will accept what is offered, instead of taking a stand and questioning the established way to deliver care,” said Dr. Marshall.

“A major focus of health-care re-form is for doctors to practice true ev-idence-based medicine and put value over volume of services. When I offer a clinical trial to a patient, I am hope-ful that it will lead to better than the standard of care. Health-care reform should not simply provide everyone with insurance to cover standard of

care, but should also force us to de-termine the true value of treatments. And in doing so, it will force us to fight a smarter war on cancer,” said Dr. Marshall.

A New Initiative to Tackle Disparities in Cancer Care

Of the approximately 7 billion peo-ple in the world, Dr. Marshall pointed out that less than 1 billion have access to cancer care. “This incredible lack of care is due largely to countries that have resources, but just not enough to support this level of health-care ex-pense. If we in the United States, the world’s richest country, cannot sus-tain our current spending on cancer, how are we going to develop a model that can deliver cost-effective cancer care to those 6 billion humans who

currently have no services?” asked Dr. Marshall. Mulling over that vast exis-tential problem led to his latest initia-tive: The Gastrointestinal Cancers Al-liance Network (GI CAN).

“I see the globalization of cancer care as an opportunity for clinicians to return to our original calling, which is to help the sick. I’m proud to be a member of the newly formed GI CAN, whose central mission is to link the stakeholders back together and de-velop common processes and systems and big data realms, hoping to shape a more equitable standard of care for the world’s underserved populations,” explained Dr. Marshall.

He continued, “A friend of mine spends about 2 weeks every year of his personal vacation time in sub-Saharan Africa providing basic medical care to people who travel by foot seeking help for a vast array of ailments. Equipped with antibiotics, some pain meds, and solid primary care skills, my friend and his associates truly make a difference in these underserved patients.”

However, Dr. Marshall emphasized that treating cancer patients is far more difficult in low-income countries.

“Without access to scanning technolo-gies, palliative care services, surgeons, and chemotherapy, I would have very little to offer a patient seeking help,” said Dr. Marshall. “When dealing with such limited resources, it’s important to develop region-specific guidelines for low-income countries, which will allocate services to those who can ben-efit from them. It’s a form of cancer care triage, but it’s necessary if we want to expand basic cancer care through-out the world.”

Acknowledging the magnitude of challenge ahead, Dr. Marshall said, “To be effective on a global scale, the alliance will initially focus on gastro-intestinal cancers, connecting emerg-ing providers in the developing world to leading cancer care and research institutions.”

When I offer a clinical trial to a patient, I am hopeful that it will lead to better than the standard of care. Health-

care reform should not simply provide everyone with insurance to cover standard of care, but should also force us to determine the true value of treatments. And in doing

so, it will force us to fight a smarter war on cancer. —John L. Marshall, MD


Andrew C. von Eschenbach, MD

“At the end of the day, I’m still a kid from South Philly,” An-

drew C. von Eschenbach, MD, for-mer Director of the National Cancer Institute (NCI) and Commissioner of the U.S. Food and Drug Adminis-tration (FDA), told The ASCO Post. Dr. von Eschenbach is the product of a closely knit yet culturally diverse household that valued caring, striv-ing, and, above all, integrity. His fa-ther was a German-American tool and die maker, and his mother was Italian American. He grew up in a tough inner-city neighborhood. “I was the first one on both sides of my parents’ families who went to college. My parents made many sacrifices be-cause they wanted my brother and me to reach our full potential. It was

Andrew C. von Eschenbach, MD, Went From the Front Lines of Cancer Care to a Bird’s-Eye View of the Changing Oncology Landscape

a passionate household. We argued over everything, including whether Joe DiMaggio was the greatest center-fielder of all time. But at the end of the day, we came away loving each other,” said Dr. von Eschenbach. He added, “My father was the consummate Ger-man craftsman; it was all about pride and precision. He stayed with every task, small or large, until it was per-fect. That philosophy would later in-form the way I approached surgery.”

Jesuit EducationWhen asked about early influences

that helped shape his career path, Dr. von Eschenbach was quick to reply, “My Jesuit education was the most transformative part of my life. I went to a Catholic grade school run by

nuns, and they ruled with an iron fist. Fortunately, I passed the high school entrance exam to St. Joseph’s Prepara-tory School. In fact I was the only kid from my grade school to get accepted.

It was a Jesuit school, and I think my first motivation to go there was to spite the nuns,” said Dr. von Eschenbach.

He continued, “After graduating from St. Joseph’s Preparatory, I went on to St. Joseph’s University. It wasn’t my first choice. I actually had my heart set on going to West Point, but I was disqualified after the admissions board discovered that I suffered from mi-graine headaches.”

Dr. von Eschenbach explained that he entered St. Joseph’s as an electronic physics major on a work co-op with RCA doing computer science but in his first year spent a bit too much

time in the old neighborhood, play-ing cards and hanging out on the cor-ner. The Dean of Freshmen, a Jesuit priest, believed in him and allowed him to enter the pre-med program

on a conditional term. “My dad and I had a lot of heart-to-heart talks over the summer. So, I began pre-med with renewed enthusiasm and wound up Class President and at the top of my class academically. I went from there, on to Georgetown Medical School,” said Dr. von Eschenbach.

He noted that the 12 years of Je-suit schooling was life-changing. “The Jesuits didn’t tell me what I was sup-posed to do with my life, but their for-mative instruction helped me develop purpose in my life’s choices. The ex-perience also gave me the realization

Instead of caring for an individual cancer patient, I’m now trying to help fix the system at large. If we fix the system, we can greatly reduce the suffering and

death from cancer and other terrible diseases such as Alzheimer’s disease.

— Andrew C. von Eschenbach, MD


NAME: Andrew C. von Eschenbach, MD

TITLE: President, Samaritan Health Initiatives, Inc; former Director, National Cancer Institute; former Commissioner, U.S. Food and Drug Administration

MEDICAL DEGREE: MD, Georgetown University School of Medicine

NOTABLE HONORS: Cancer Leadership Award, Friends of Cancer Research (2004); National Healthcare Humanitarian Award, Patient Advocate Foundation (2005); TIME Magazine’s 100 Most Influential People (2006); Modern Healthcare Magazine’s 17th Most Powerful Person in World Health Care (2007); Shield of Loyola, St. Joseph’s University (2008); Secretary of Defense Medal for Exceptional Public Service (2009); The Texas Philosophical Society (2009)

Global Collaboration Needed“We as a community talk a lot

about lung cancer, breast cancer, and prostate cancer, but collectively gastrointestinal cancers are the most common and most fatal cancers on the planet. And as a community, we have failed to discover the driving mutations behind these malignancies. Consequently, industry has lost much of its interest in certain gastrointesti-nal malignancies. In effect, the gastro-intestinal community has dug itself

cer care infrastructure. And as we find increasingly effective therapies in a more cost-efficient manner, we hope to reach a value point that will be af-fordable for all people around the world.”

Asked for a closing thought, Dr. Marshall offered, “If I could have one eternal gift for Christmas, I would wish for a Sorting Hat. For those un-familiar with Harry Potter books, a Sorting Hat is used as a sort of ‘soul biopsy’ for the new kids at Hogwarts School of Witchcraft and Wizardry, which assigns them to one of the four

specialty houses. That’s what we re-ally need in oncology. I want an un-flawed test that houses my patients and tells me what their future really holds. Then I wouldn’t need the trial-and-error empirical methodology we use today. It would remove the mys-tery and allow me to make precise decisions.”

He paused a moment and added, “Our obligation and duty is not to try to add just a month or two of survival with a new medicine but to have dra-matic impact; patients are expecting us to cure them.” n

into a hole,” said Dr. Marshall.Coming back to GI CAN, Dr. Mar-

shall said, “To develop effective treat-ments for gastrointestinal cancers, we need massive information-sharing data sets. No one center or coopera-tive group or nation has enough pa-tients for this kind of discovery. So, a central part of GI CAN’s effort is to create a platform of collaboration among major academic institutions, IT companies, and the pharmaceu-tical industry to reduce the cost of clinical trials. We seek to simplify the process and set up a global can-

John L. Marshall, MDcontinued from page 32


that to those to whom much is given, much is expected.”

Path to MedicineAfter receiving his medical degree

from Georgetown University School of Medicine in 1967, Dr. von Eschen-bach served in the U.S. Navy Medical Corps from 1968 to 1971, during the Vietnam War. “I loved being a na-val medical officer. I was assigned to Washington, DC, and seeing the sac-rifice that our servicemen and their families made was inspiring. I was a general medical officer, and much of my job centered on trying to aid the healing process.”

He commented that the experi-ence he got in the Navy served as a solid foundation as he entered his residency at Pennsylvania Hospital in Philadelphia in general surgery and urology. “I was really passionate about surgery, especially urology, which was filled with intricate procedures. I had a fantastic residency experience with the best mentor, but I became espe-cially focused on oncology. I was in-tellectually fascinated by cancer and truly wanted to do something about the suffering and death caused by the disease,” said Dr. von Eschenbach, adding, “So that’s why I ventured into urologic oncology.”

Dr. von Eschenbach had planned to do his oncology fellowship at Memo-rial Sloan Kettering Cancer Center, but his wife, Madelyn, wasn’t thrilled about rearing their four children in a Manhattan apartment. Serendipi-tously, a University of Pennsylvania professor of Dr. von Eschenbach's who had gone down to Houston to head the urology department at the medical school suggested that he apply for a fel-lowship at The University of Texas MD Anderson Cancer Center.

“The annual American Urological Association meeting was in Dallas, so after the meeting I went to Houston to see MD Anderson Cancer Center and was literally bowled over by the experi-ence. I applied for a fellowship position and was accepted. So, we packed up the kids and moved to Texas, telling every-one back home in Philly that we’d be back in a year,” said Dr. von Eschenbach.

It was during this transitional pe-riod in Dr. von Eschenbach’s life that his father, who had been diagnosed with prostate cancer, progressed to

castration-resistant metastatic disease. “I brought him to MD Anderson for treatment. He was put on the first ever randomized national chemotherapy clinical trial for prostate cancer, but he shortly progressed to end-stage cancer and chose to go back home to fam-ily and friends in Philly. At the time, I

was asked to accept a faculty position at MD Anderson, but I also faced a huge internal battle knowing that my father was going home to die. But my dad said, ‘Your mom and I worked our whole lives to give you an opportunity to do something special, and if you be-lieve that staying here at MD Anderson

Andrew C. von Eschenbach, MDcontinued from page 33

helps that goal, then I want you to stay. Coming home is not going to change what’s going to happen to me.’”

Pushing the Boundaries of Oncology

Dr. von Eschenbach stayed at MD Anderson, becoming Assistant Pro-

www.bostonbiomedical.com

Malignancies, like normal adult tissue, have been shown to contain a subset

of cells that have the capacity to both self-renew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6

Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence.

Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10

Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

Understanding Cancer Stem CellsCancer Stem Cells Signal Pathways Regrowth Metastasis

EDU-NPS-0009 12/2014 ©2014 Boston Biomedical

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fessor in 1977, and by 1983, he was Chairman of the Urology Depart-ment. He described the MD Ander-son experience thusly: “When I first walked in the door as a fellow, it was like an airport at rush hour. People were pushing gurneys with IV poles and patients with radiation tattoos on

their faces, and I felt an overwhelm-ing sense of sadness. But I only felt that way for one day, because I real-ized that I had the privilege to be a member of a great institution that was pushing the frontiers and chang-ing the world of oncology.”

“For instance, I was part of an

experience, over 10 or 15 years, in which a diagnosis of metastatic tes-ticular cancer went from being a death sentence to seeing men survive and be cured. It was amazingly grati-fying,” said Dr. von Eschenbach.

Dr. von Eschenbach said that dur-ing his 26-year tenure at MD Ander-

son, he got to see the birth of molec-ular medicine. “We were unlocking the secrets of the cancer cells and it became obvious that if we could fully understand the underlying mecha-nisms of the disease, we could strategi-cally move forward in eliminating the majority of suffering and death due to cancer,” stressed Dr. von Eschenbach.

National Cancer Institute Tenure

Although fiercely dedicated to his work at MD Anderson, Dr. von Eschenbach wanted to make a differ-ence on the national scale, which was made possible when he was given the opportunity to head the NCI. “Moving to the NCI was like going from boots on the ground, during which I was on the front lines of day-to-day can-cer care, to being a pilot in an AWAC surveillance plane, where I got to see the whole landscape of oncology,” ex-plained Dr. von Eschenbach.

In 2001, Dr. von Eschenbach was selected as NCI Director by President George W. Bush. Dr. von Eschen-bach’s only regret was that he would have to leave his surgical career, which he was passionate about. “The day that I traded in my white coat for a suit was painful. And it still is,” said Dr. von Eschenbach. But, he added, “we have the ability within our grasp, based on the trajectory of progress, to expand our understanding of the fun-damental mechanisms that give rise to our susceptibility to cancers, the early events of malignant transforma-tion, the progression and the meta-static spread, and the ultimate death that we see all around us. Conquering cancer is doable.”

Modernizing the FDAFour years later, Dr. von Eschen-

bach was in his office when the tele-phone rang. “It was the White House saying that there’s a problem at the FDA and the President wanted me to take over the Agency. I said that I couldn’t just walk out on the NCI, so they said fine, I could do both jobs un-til we find a resolution. For 6 months, I was NCI Director and Acting FDA Commissioner. It was hectic. In truth, the NCI is a well-oiled machine, but the FDA, at that time, was in a crisis of being understaffed and overbur-dened. That’s where I was needed, and I stayed on as a Senate-confirmed Commissioner.”


www.bostonbiomedical.com

Malignancies, like normal adult tissue, have been shown to contain a subset

of cells that have the capacity to both self-renew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6

Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence.

Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10

Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

Understanding Cancer Stem CellsCancer Stem Cells Signal Pathways Regrowth Metastasis

EDU-NPS-0009 12/2014 ©2014 Boston Biomedical

ADVERTORIAL

06111A_R3_BBI_Advertorial_Island.indd 1 12/30/14 3:01 PM

http://www.bostonbiomedical.com/home


Wyndham H. Wilson, MD, PhD

“Dear Dr. Wilson: I am writing to express our family’s deepest and

heartfelt appreciation for the lifesaving care you and your team provided for our son, Patrick…. I don’t know how widely it is known that you save lives at the Na-tional Cancer Institute—offering hope to people like Patrick, who have run out of options.”

So begins a letter addressed to Wyndham H. Wilson, MD, PhD, from a father whose son Dr. Wilson and his team had successfully treated for central nervous system lymphoma. Dr. Wilson, an internationally regard-ed expert on lymphomas, has spent the better part of his notable career at the National Cancer Institute (NCI). His life’s work has given the medical world a much clearer understanding of the complexity of lymphoma.

A Childhood AbroadDr. Wilson’s father was an aca-

demic surgeon who sought to bring high-value medicine to countries in

Wyndham H. Wilson, MD, PhD: Shedding Light on the Complexity of Lymphoma Through a Lifetime of Illuminating Research

the developing world. “I was born in San Francisco, but when I was about 1 year old, we relocated to Lebanon, and my father assumed a position at the American University of Bei-rut, where he was the dean of the medical school and head of the sur-gical department. I grew up on the university campus in Lebanon and remained there until the age of 17,” said Dr. Wilson, adding, “I had an

interest in medicine, probably from the time I was 4 years old. I used to accompany my father as he made

rounds in the laboratories and read everything I could that had to do with anatomy or science.”

Dr. Wilson attended an inter-national school in Beirut called the American Community School, which provided education for chil-dren from kindergarten through 12th grade. “Back then there were a lot of kids whose parents were as-sociated, in one way or another, with

the diplomatic service or the oil in-dustry in the Arab Gulf states. I’d say that about 80% of the students were American, as were most of the teach-ers. The rest of the teachers were pre-dominantly from Europe, although there were a few Arabic teachers, too. I’d liken the quality of education to a good American preparatory school. The school is still fully operative to this day,” said Dr. Wilson.

Seeking Stability at StanfordHaving left the United States at

such an early age, Dr. Wilson was spared the separation anxiety older children often suffer during a major move from home. “I actually felt up-rooted at 17 years old when we left Lebanon, feeling like I’d been moved to a completely alien environment, which was the United States. We set-tled in Palo Alto, California, where my mother was originally from, and my father took a position as Professor of Surgery at Stanford University,” said Dr. Wilson, adding, “I finished up my last 2 years of high school at the Palo Alto High School and then applied for college.”

Asked to describe his college ex-perience, Dr. Wilson said, “There was never much thought about where I was going to go, so I ap-plied to one university: Stanford. I received a combined BA (human biology) and MS (biology) in 1975, and an MD and PhD (neurobiology) in 1981 from Stanford University. I then completed my internship and residency training at Stanford as well. I’d found the move from Leba-non back to the States very disrup-tive, which was one reason that I stayed at Stanford throughout my college and medical schooling, hav-

During the clinical trials in the early 1990s, I was writing my own studies and virtually running them on

my own. Fast forward to the present, and we are running multiple studies across all phases, which all have

complicated translational components to them. — Wyndham H. Wilson, MD, PhD

NAME: Wyndham H. Wilson, MD, PhD

TITLE: Head, Lymphoma Therapeutics Section, and Senior Investigator, Lymphoid Malignancies Branch, National Cancer Institute

MEDICAL DEGREE: MD, Stanford University School of Medicine; PhD, Stanford University

During his 3 years as FDA Commis-sioner, Dr. von Eschenbach employed an agenda to modernize the FDA. Un-der his leadership, he emphasized the FDA’s role in working with external partners to ensure quality throughout the entire life cycle of the products it regulates, while internally fostering a regulatory pathway that is transpar-ent and efficient but still rigorous and science-led.

“As FDA Commissioner, I traveled the world, collaborating with heads of other regulatory agencies, includ-ing opening the first FDA offices out-side the United States in China, India, Latin America, and Europe, and gath-ered incredible insights into things we hadn’t seen or appreciated yet. I had an ‘oh-my-God’ moment, realizing that if we optimize our understanding of the fundamentals of life at the genomic, molecular, and cellular levels, we’ll be able to transform our world, not just in medicine and health care, but in agri-

culture and the environment,” said Dr. von Eschenbach. “With the sequenc-ing of the human genome, we turned biology into a digital science. The pos-sibilities are endless, if we work togeth-er to seize the potential.”

Now, President of Samaritan Health Initiatives, Inc, Dr. von Eschenbach ad-mits that he misses government work, especially the FDA, which he calls a remarkable institution loaded with talent and dedication. Asked about his current work, he replied, “I’m still trying to make a difference in peoples'

lives. It was the same thing I wanted to do when I was in high school. I’m just doing it in a different way. Instead of caring for an individual cancer patient, I’m now trying to help fix the system at large. If we fix the system, we can greatly reduce the suffering and death from cancer and other terrible diseases such as Alzheimer’s disease.”

Dr. von Eschenbach, still a kid from south Philly, has been married to his childhood sweetheart, Madelyn, for 48 years. They have four children and seven grandchildren. n

Andrew C. von Eschenbach, MDcontinued from page 35


ing no desire to move about. I liked the stability Stanford offered,” said Dr. Wilson.

Asked about his decision to pur-sue a career in oncology, Dr. Wilson said, “As a young boy I’d not only been interested in medicine, but I also had an interest in science. I went to school in the 1970s, finishing up in the early 1980s, a time when oncolo-gy was beginning to make significant strides in research and treatment. And for the first time, we were be-ginning to understand the molecular basis of cancer, so I became intrigued by the science behind oncology and the possibilities ahead both in the lab and the clinic.”

Mentors at the NCIHe continued, “At that time, Stan-

ford was heavily into lymphoma re-search. In fact, early on in medical school, I’d applied to a number of on-cology fellowships, focusing on the top lymphoma groups. Interestingly, I was turned down by Stanford but was ac-cepted by the NCI, which turned out to be a career-defining move. I finished my residency at Stanford and went to the NCI in 1984.”

Dr. Wilson explained that, as in any fellowship program, the first year at the NCI was consumed by a lot of “drudge” work, but in the ensuing years he found the NCI to be an environment that en-couraged fellows to engage in research, which was his primary focus.

“After doing the clinical part of the fellowship, I went on to do my re-search years, during which I had two terrific mentors, who helped my ca-reer path mature. First there was Dr. Dan Longo, and then some time later, Dr. Bruce Chabner. It was while work-ing under these two great doctors that I truly developed my core instincts in how one should approach cancer research and the scientific methods for conducting studies, which have stayed with me to this day. Although I did my PhD in neurobiology, at the NCI, my work was focused on protein chemistry,” said Dr. Wilson.

The Importance of Solid Trial Design

“Even though I ultimately moved more toward the translational end of research with very deep roots with laboratories, I personally do not run a lab. I’m concerned with developing many of the concepts of design and hypotheses so that the trials can give

us clear outcomes, whether positive or negative. I find that many of the clinical trials underway are not really thought through and are just empiri-cally derived. In such, much of what we could learn from trials is simply lost,” said Dr. Wilson.

Dr. Wilson began his fellowship at the NCI in the “Golden Era” of groundbreaking discovery, a time of less paperwork and far fewer road-blocks on the road to cancer drug development. Asked to compare and contrast the 1970s with con-temporary drug development, Dr. Wilson responded, “The challenges in the drug development process have become much greater. Interest-ingly, the core for what is necessary for institutional review board ap-proval was actually developed in the 1980s and 1990s. But the approval process is essentially just guide-lines, and how they are interpreted and implemented is really what has changed over the past few decades. Clearly, guidance has become more specific, but the core messages re-main the same.”

“Unfortunately, much of the gener-al language in the early guidelines has been, if you will, filled in. Although the safety regulations and integrity of the guidance have increased, the oversight needs and the amount of ancillary people needed to help weed through all of these regulatory issues have also

increased enormously, such so that it has made the approval process very sluggish,” he said.

A Day in the LifeDr. Wilson, who is currently the

Head of NCI’s Lymphoma Therapeu-tics Section and a senior investigator, has been at the Institute for the major-ity of his career. He commented that when he first began the Lymphoma Therapeutics Section, it was basically a one-man show.

“During the clinical trials in the early 1990s, I was writing my own studies and virtually running them on my own. Fast forward to the pres-ent, and we are running multiple studies across all phases, which all have complicated translational com-ponents to them. I’ve amassed a staff of physicians, researchers, research nurses, and data managers to run these clinical trials. I provide over-sight to the operations and intellec-tual foresight into the future. More-over, there has become an increasing need for me to interact with indus-try at an earlier stage of a drug’s life cycle. The NCI provides a lot of the intellectual structural underpinning for trial development, and we work with industry,” explained Dr. Wilson. “I also work closely with Dr. Louis Staudt, one the world’s foremost lymphoma experts,” he added. In es-sence, he and I closely collaborate to

translate his basic observations and conversely to provide translational endpoints for hypotheses that come from our clinical studies.”

When Dr. Wilson isn’t at the NCI running the lymphoma section, he’s usually in an airport. “I do a lot of trav-eling to lecture on our work at the NCI and serve on various committees, such as chairing the U.S. Food and Drug Administration Oncologic Drug Ad-visory Committee, which I completed several years ago. So I have a fairly full schedule,” said Dr. Wilson.

As a researcher who has seen an incredible arc of knowledge and dis-covery in oncology over the course of his esteemed career, have the modest gains in survival we’ve seen in some cancers dampened his outlook for the future? “Absolutely not. In fact I’m more optimistic now than ever,” Dr. Wilson maintained. “One very bright light has been the renewed in-terest in immune therapy. Although we’ve known that the immune sys-tem can help eradicate subclinical cancers, we’ve reached a point in which we feel we can harness the im-mune system, perhaps in conjunc-tion with targeted biologics, and see major advances in curative therapies. Another thing that makes immuno-therapy so exciting is that it is not pathway-specific. There is no reason for us in the oncology community to be anything but optimistic.” n

2016 GrantsOpen June 3, 2015

Apply by September 2, 2015 lymphoma.org/grants

For Early Career Investigators: - Clinical Investigator Career Development Award - Postdoctoral Fellowship Grant - Lymphoma Clinical Research Mentoring Program

For Senior Investigators: - Follicular Lymphoma Pathways Grant

http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=8490965


Robert C. Young, MD

Robert C. Young, MD, ASCO Past President, longtime leader

of Fox Chase Cancer Center, and an internationally recognized expert in lymphoma and ovarian cancer, is a for-ward-looking doctor who is confident about something not in his future: re-tirement. “I’ll never quit working; I’m just not wired that way,” Dr. Young told The ASCO Post.

Finding a Natural Fit in Medicine

Dr. Young grew up in Columbus, Ohio, the son of a solo-practicing surgeon. “Although most people don’t jump at the idea of following in one of their parent’s footsteps, I did. My father practiced in the golden age of surgery, a time of huge advances, and he was extraordinarily happy with his career. On weekends, he’d take me on hospital rounds. It was incredibly exciting, and seeing how much my father enjoyed tak-ing care of his patients rubbed off on me. So, wanting to become a doctor was a natural thing for me, and I nev-er swayed from it,” said Dr. Young.

Throughout high school, Dr. Young’s interest in medicine and sci-ence continued to grow. After grad-uating, he went to Ohio State Uni-versity, which he said was “about 5 minutes from my home.” In contrast to the extravagant nail-biting college process in which today’s applicants and their parents go through, Dr. Young explained that in his youth,

After a Long and Distinguished Career, Robert C. Young, MD, Shows No Sign of Slowing Down

it was a much simpler affair. “I don’t think I applied to another college. Ohio State was a good school and it was right around the corner. Also, at that time any kid who graduated from a credible high school could go to a state school. It just wasn’t a big deal,” said Dr. Young.

The sheer size of Ohio State’s campus and the variety of subjects offered intrigued Dr. Young. “Dur-ing my premedical courses, I could fit in a bunch of political science, history, and economics courses also. I became very interested in student government and campus politics, and in my senior year I was elected president of the student body,” said Dr. Young, adding, “Ohio State was a great experience in that I got to study a full range of subjects that truly broadened me as a person, be-fore I got to med school, because then it was medicine from morning till night.”

After graduating from Ohio State in 1960 with a BSc degree in zool-ogy, Dr. Young felt the urge to leave his home state and attend medi-cal school somewhere other than the Midwest. “My father had gone to Harvard Medical School, and he wanted me to also. I applied to sev-eral top schools, Harvard included; I was accepted at Harvard and was also accepted at Cornell University Medical College. I had some friends there, and quite frankly the idea of living in New York City was very

appealing. So that’s where I went, which was kind of a bummer for my dad. But I explained that when I went on interviews at Harvard, it just didn’t seem like the right fit, and he understood,” said Dr. Young.

Although Dr. Young’s first incli-nation was to become a surgeon, once at Cornell, he became very in-terested in research, especially in the laboratories doing work in hematol-ogy. “In those days, every member of the faculty wanted grants, and compared with today, they were easy

to get. And a researcher could give a young medical student $500 to work all summer in his lab, and that’s what I did during my summers. Early on, I decided that instead of surgery, I wanted to do internal medicine,” said Dr. Young.

From Hematology to Oncology at the NCI

It was the early 1960s, and the Vietnam War was raging. To fill the military’s need for soldiers during a hugely unpopular war, the draft was casting an ever-widening net. Dr. Young explained that a physician coming out of medical school had few choices. “One was taking your chance with the draft, which at that time was very risky. Then there was the Berry Plan, in which you deferred your mili-tary obligation until after you finished your residency. I was in my senior year, so it was getting close to crunch time. I was working in a hematology lab, and a senior clinician suggested

I look into the National Institutes of Health’s (NIH) public health service programs because they exempt you from the draft,” said Dr. Young.

He was eager to continue his he-matologic research while avoiding the draft, so he applied to the very competitive NIH program and was accepted into the clinical associate program at the National Cancer In-stitute (NCI), which, in effect, trans-ferred his activities from hematology to oncology. After 2 years in the NCI program, Dr. Young took a senior

residency position at Yale University. In 1970, he received an invitation from the NCI to serve in its medicine branch after he finished his residency, a tough decision at the time.

“Although I had a number of solid options, the NCI position seemed to be the most interesting, so I took it, and it turned out to be the second best decision I’ve ever made, the first being marrying my wife. As luck would have it, I returned to the NIH in 1970, the year before the National Cancer Act was signed, so there was a huge increase in funding and many opportunities to get involved in the latest research. I was part of a group of five investigators that developed the first curative regimens for Hodgkin lymphoma and diffuse ag-gressive lymphomas,” said Dr. Young, adding, “We were called the ‘Gang of Five,’ and of that gang, four of us be-came ASCO presidents: myself, Vince DeVita, George Cannellos, and Phil Schein. Bruce Chabner, the fifth, also had an equally distinguished career

Until the federal government…addresses entitlement spending, the NCI, which is funded by discretionary

spending, will continue to get its funding shortchanged. That’s catastrophic for the future of cancer research.

— Robert C. Young, MD

NAME: Robert C. Young, MD

TITLE: President, RCY Medicine

MEDICAL DEGREE: MD, Cornell University Medical College

NOTABLE HONORS: Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research (2002); ASCO Distinguished Service Award for Scientific Leadership, ASCO (2004); American Association for Cancer Research Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research (2013)


as Director of the Division of Cancer Treatment and Clinical Director of On-cology at Massachusetts General Hos-pital,” said Dr. Young.

Dr. Young was at the NCI for about 17 years. Toward the backend of his tenure, on a request from Dr. DeVita, who was NCI Director at the time, Dr. Young took charge of the cancer centers branch, which gave him the opportunity to visit many of the coun-try’s centers. “We wanted to see how the centers could best leverage the scientific information coming out of the NCI. When at Fox Chase Cancer Center, Dr. Young met the president, John R. Durant, MD, who was leaving his position. “John suggested I take a look at filling his position as Fox Chase President and CEO. I was interested, and after several meetings with the board, I was offered the position. In a sense, I’ve had two jobs my whole life, Chief of the Medicine Branch at NCI, and President and CEO of Fox Chase,” said Dr. Young.

The Evolution of ASCOIn 1989, Dr. Young served as Presi-

dent of ASCO, which was a much different organization than today’s global leader in oncology. “The first meeting that I attended at ASCO was

in 1968 and we had about 200 people. It was a half-day session immersed in the American Association for Cancer Research (AACR) meeting. We were still a fairly small enterprise at that point, and most of the data were from simple trials, testing the application of chemotherapy to a variety of tu-mors,” said Dr. Young.

By the time he was President in 1990, the ASCO Annual Meeting had grown to about 4,000 attendees strong. “We finally broke from the AACR and had our own meeting, and it was a full meeting with a lot of randomized trials being presented and a lot of basic science data being explored. Looking back, it’s hard to believe but it was during my presi-dency that the Society hired its first full-time employee and set up an of-fice in space owned by an indepen-dent law firm. Prior to that, ASCO’s meeting was managed by an event planner. So this was really the begin-ning of ASCO as an independent or-ganization managing its own enter-prise,” said Dr. Young.

He continued, “Up until then, ASCO had always been seen as an aca-demic oncology organization, with a clinical emphasis. It became clear that we needed to involve private practice

oncologists more actively. However, there was tension between the aca-demic and private practice worlds. My father was a clinical academic profes-sor, but he was also a private practitio-ner, so I had previous experience with the issue. We set up an ASCO commu-nity affairs committe and asked Dr. Joe Bailes, a prominent community on-cologist, to chair it. And since then, the Society has made every effort to bal-ance the needs of both academic mem-bers and those in clinical practice.”

Looking Back, Looking Forward

Asked what have been the major advances over the course of his career, Dr. Young responded, “First would be the cure of childhood leukemia, cer-tain lymphomas, and testicular can-cer. These advances proved that che-motherapy can cure some systemic cancers. The second major advance was the use of adjuvant therapy in common cancers such as breast and colon cancers. The third was the ba-sic understanding of the biology and mechanisms that drive cancer causa-tion. And finally, I’d cite the hugely successful anti-tobacco campaign that has occurred over my lifetime, saving millions of lives.”

Dr. Young currently works inde-pendently in the consulting field, covering a wide array of needs and venues, from cancer centers to the pharmaceutical industry. “My work allows me to continue addressing problems that I find interesting and challenging. I like to stay up-to-date and fully immersed in the exciting world of oncology,” said Dr. Young.

He added a cautionary note, “I wor-ry deeply about the NIH funding issue. Until the federal government, no mat-ter which party is in charge, addresses entitlement spending, the NCI, which is funded by discretionary spending, will continue to see its funding short-changed. That’s catastrophic for the future of cancer research.”

Does Dr. Young’s busy schedule al-low some time for unwinding with lei-sure activities? “I like to connect with my daughters and my five grandchil-dren, and I’m an avid birdwatcher, so I do quite a bit of birding. I also travel to meetings. In fact I was at the recent AACR meeting and caught up with Bruce Chabner there. Our wives came along so they had breakfast together,” said Dr. Young.

Two of the “Gang of Five” still shar-ing time at a scientific cancer meeting. Some things never change. n

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All submissions will be considered for publication

Mrs. Thomas enrolled in the medical technology training pro-gram at New England Deaconess Hospital. She worked as a medical technician for some doctors in Bos-ton until eventually Dr. Thomas had his own laboratory, and then she be-gan to work with him.

“Dottie was there at Don’s side through every part of developing mar-row transplantation as a science,” said Fred Appelbaum, MD.

Dr. Thomas joined Fred Hutchin-son in 1975, the year its doors opened in Seattle’s First Hill neighborhood. For the next 15 years, Mrs. Thomas served as the Chief Administrator for the Hutchinson Clinical Research Di-vision. Dr. Thomas stepped down from the clinical leadership position in 1990 and retired from Fred Hutchinson in 2002. ❧

John H. Saiki, MDDecember 31, 1936–August 8, 2014

John “Jack” Harris Saiki, MD, Professor Emeritus at the University


of New Mexico Department of Medi-cine, Hematology/Oncology Divi-sion, lived the history of modern-day oncology with a career spanning 44 years. In the early days of his career, with the support of a grant from the

federally funded New Mexico Region-al Medical Program, Dr. Saiki devel-oped a leukemia-lymphoma treatment program at a time when no formal medical oncology program existed in New Mexico.

Dr. Saiki received his medical de-gree from McGill University in Mon-treal, Canada, in 1961. Dr. Saiki served 2 years with the U.S. Public Health Service in Fort Defiance, Arizona. He completed his residency and fellowship

training in medicine and hematology at the University of New Mexico School of Medicine and his oncology training at The University of Texas MD Ander-son Cancer Center. Dr. Saiki joined the faculty at the University of New Mexico School of Medicine in 1970.

Dr. Saiki was subsequently award-ed funding from the National In-stitutes of Health in support of his membership in Southwest Oncology Group (SWOG), which ushered in cancer clinical trials and new can-cer treatments for New Mexicans. In 1973, Dr. Saiki received Board certi-fication in medical oncology, the year the subspecialty of medical oncology was first created.

Dr. Saiki served in various capaci-ties while on the faculty, including Clinical Director of the University of New Mexico Cancer Center and Principal Investigator for the SWOG. In addition, Dr. Saiki served on the Board of Trustees for Blood Systems for 29 years and was Medical Director of the Presbyterian Hospice Program.

Dr. Saiki was the recipient of nu-merous awards for teaching and ser-

vice, including the Laureate Award by the New Mexico Chapter of the Amer-ican College of Physicians and nine Khatali Awards, an honor bestowed by each graduating class of the University of New Mexico School of Medicine in recognition of teaching excellence. A celebration of Dr. Saiki’s life was held at the University of New Mexico Can-cer Center. n

John H. Saiki, MD


June13th International Conference on Malignant Lymphoma (ICML)June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

Yale ASCO® Review 2015: Highlights of the Annual MeetingJune 19 • New Haven, Connecticut For more information: https://transact.med.yale.edu/cme/conferences/conference_index.asp?ID=1149&linkID=0

EACR-AACR-SIC Special Conference June 20-23 • Florence, Italy For more information: www.ecco-org.eu/eas2015

Anticancer Drug Action and Resistance: From Cancer Biology to the ClinicJune 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

CAP-ACP 2015 Annual MeetingJune 20-23 • Montreal, Canada For more information: www.cap-acp.org

International Conference on Prostate CancerJune 22-24 • Orlando, Florida For more information: http://prostatecancer.cancersummit.org

International Society on Thrombosis and Haemostasis Annual MeetingJune 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

The World NSCLC Summit 2015 BostonJune 23-24 • Boston, Massachusetts For more information: http://nsclc.skygenix.com

MASCC/ISOO Annual Meeting on Supportive Care in CancerJune 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

ASCO Review 2015June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/courses/2015/ASCO15/default.asp

2nd EACR Special Conference on Cancer GenomicsJune 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org

IO360–Immuno-Oncology 360o

June 29-June 30 • New York, New York For more information: http://theconferenceforum.org/conferences/immuno-oncology-360/overview/

July

7th World Congress on Gastrointestinal CancerJuly 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/WGIC2015/index.asp

Gynecologic Oncology GroupJuly 15-19 • Denver, Colorado For more information: www.gog.org/meetinginformation.html

14th Annual International Congress on the Future of Breast Cancer®July 16-18 • Huntington Beach, California For more information: www.gotoper.com

NRG Oncology MeetingJuly 16-19 • Denver, Colorado For more information: www.gog.org/meetinginformation.html

Palliative Medicine and Supportive Oncology 2015July 23-25 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/courses/pallmed15/overview.asp

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-OncologyJuly 28-August 1 • Washington, DC For more information: www.apos-society.org

16th Annual International Lung Cancer Congress®July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/meetings/16th-International-Lung-Cancer-Congress

Best of ASCO® BostonJuly 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

AugustBest of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://boa.asco.org/

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

World Congress on Cancer and Prevention MethodsAugust 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/oncology-2015/

ASCO Multidisciplinary Cancer Management Course (MCMC)August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/international-programs/multidisciplinary-cancer-management-courses

European Society for Medical Oncology Academy 2015August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September2015 World Molecular Imaging CongressSeptember 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/

International Palliative Care WorkshopSeptember 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/international-palliative-care-workshops

25th World Congress of the International Association of Surgeons, Gastroenterologists and OncologistsSeptember 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

ILCA 2015 —The International Liver Cancer Association’s 9th Annual ConferenceSeptember 4-6 • Paris, France For more information: www.ilca2015.org

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

25th World Congress of LymphologySeptember 7-11 • San Francisco, California For more information: www.lymphology2015.com

American Society of Head and Neck Radiology (ASHNR) Annual MeetingSeptember 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

American Society of Hematology (ASH) Meeting on Hematologic MalignanciesSeptember 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/

4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015)September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/childhood-cancer/CIPO-2015/

2015 Oncology Meetings 2015


James F. Holland, MD

A Tribute to James F. Holland, MD, in Celebration of His 90th Birthday

Delafield Cancer Center at Columbia, spring 1953. Top left to right: Elliott Osserman, MD, Alex Sahagian-Edwards, MD, Tony Choy, MD, Jack D. Davidson, MD, Don Tschudy, MD. Bottom left to right: James Holland, MD, his mentor Alfred Gellhorn, MD, Nadine Luxmore, RN, and George A. Hyman, MD

Far and away the best prize that life has to offer is the chance to work hard at work worth doing.

—Theodore Roosevelt

Longevity, in and of itself, is not an accomplishment. Luck and good

genes are just human lottery tickets. Most people fortunate enough to live long lives have a productive sweet spot in their chronology, and as they grow older they cherish the memory of that distant part of their lives. Then there are the rare people who tend to sus-pend time, never letting nostalgia get in the way of the important work ahead. One such person is oncology luminary James F. Holland, MD, Distinguished Professor of Neoplastic Diseases in the Department of Medicine at the Icahn School of Medicine at Mount Sinai in New York. Dr. Holland celebrated his 90th birthday on May 16, 2015.

“Dr. Holland has always been a true leader and an inspirational figure, will-ing to tackle the toughest problems. On his 90th birthday, he is still chal-lenging the conventional wisdom with his continuing research,” said oncology pioneer Emil J. Freireich, MD, of his colleague.

A Career Path Is SetDr. Holland was born on May 25,

1925, in Morristown, New Jersey, where he grew up as the second young-est of four boys. He decided early on to become a doctor. After graduating from Columbia University College of Physicians and Surgeons and complet-ing his residency, Dr. Holland served as a captain in the U.S. Army Medical Corps during the Korean War.

“I was set to begin my medical staff rotations,” Dr. Holland explained, “but I had to stay in the Army longer than expected because President Truman ex-tended everyone’s tour of duty. I wrote the Chair of Medicine at Columbia Pres-byterian Hospital and said I wouldn’t be

back by July 1, which is when the staff rotations began. He wrote back to me saying that he couldn’t save a place for me because he needed the house to take care of patients. However, they’d just opened a new cancer hospital called Francis Delafield, run by Columbia and paid for by the City of New York, and the Chair assured me he’d place me there after somebody dropped out for tuberculosis or psychiatric reasons.”

Dr. Holland and many of his other celebrated friends and colleagues be-gan their groundbreaking work before oncology had been established as a formal medical discipline; in those days, choosing oncology as a profes-sion was for a select few visionaries. Oftentimes serendipity plays a role in the weighty decision of one’s career choice; in Dr. Holland’s case, that ser-endipity came in the form of a patient by the name of Jennifer.

“I left the Army at the end of Sep-tember. There was no formal fellow-ship in medical oncology at the time, but I worked under the aegis and su-pervision of Alfred Gellhorn, MD, who was my mentor at the Francis

Delafield Hospital at Columbia Uni-versity in New York. While there, I had a 4-year-old patient named Jenni-fer who had acute leukemia. I treated

her with aminopterin, and she went into remission. It was fantastic to see this drug work. When the Chair of Medicine from Columbia Presbyte-rian called me to say that a place had opened up for me, I thanked him and

said I’d decided to stay at the cancer hospital. That’s when I really decided on oncology,” said Dr. Holland.

A New Era of ChemotherapyIn 1953, Dr. Holland joined the Na-

tional Cancer Institute (NCI). Up un-til then, the NCI had locations across the country, but when the Institute was centralized on the National Institutes of Health (NIH) campus, it generated an intense atmosphere of collective scientific research. “I was a medical officer and perhaps the most senior clinician. My immediate superior was Leonard Fenninger, who I think was Chief of the Medical Service, and at the time G. Burroughs Mider was the Acting Clinical Director. I ran research activity primarily in acute leukemia at the time, and some junior colleagues who had just finished their residency joined me,” explained Dr. Holland.

He continued, “Dr. Mider intro-duced me to Lloyd Law, PhD, who had shown that in leukemic mice, a combination of drugs given at the same time was better than when giv-en in sequence. Dr. Law and I became wonderful friends, and I learned a lot


An important part of being able to sustain oneself in oncology is to have the camaraderie of fellow oncologists, kindred souls…who are facing the same challenges and

who understand. ASCO has served wonderfully for me and for many others to maintain the recognition that we are

all in this long and difficult chore together —James F. Holland, MD


about science from him. So I contin-ued research in combination therapy, and when it became clear that mer-captopurine and methotrexate were two clinical drugs that were active in childhood leukemia, I put together a protocol with Dr. Law’s approbation.”

William Newton, MD, of the Chil-dren’s Hospital in Columbus, Ohio, and Dr. Holland were the first re-searchers to give those two drugs in combination. “The strategy was based on the concept that about one-third of patients responded to methotrex-ate and about one-third responded to mercaptopurine, so theoretically, one

in nine might be sensitive to both and conceivably achieve a cure. It was the beginning of a new era in chemothera-py,” said Dr. Holland.

Reflecting on his friend and col-league’s immense contribution to oncology, Vincent T. DeVita, MD, noted, “Jim Holland is one of the founding fathers of cancer chemo-

therapy. Without his ebullient sup-port and his leadership of the coop-erative group Acute Leukemia Group

B, the work on childhood leukemia might have gone unnoticed. His work confirmed the curative potential of combination chemotherapy. He is also one of a stellar group of trainees of the great Alfred Gelhorn, Direc-tor of the Delafield Cancer Center at Columbia, which included John Ultmann, Paul Marks, Franco Mug-gia, Helen Ranney, Elliott Osserman, George Hyman, and others.”

Dr. Holland served at the NCI from July 1953 to November 1954. Dr. Freireich, another founding fa-ther of combination chemotherapy, reflected on his colleague’s legacy. “Dr. Holland, who preceded me at the NCI, had attracted several chil-dren with acute leukemia and had begun treating them with the che-motherapeutic agents then available. Over the next 10 years I developed combination chemotherapy regimens that resulted in a cure for a fraction of children, and it was the first systemic metastatic cancer to be cured. So the high point of my career was attributed to Dr. Holland’s foresight in leaving the children under my care.”

Personal and Professional Fulfillment at Roswell Park

After receiving a job offer at Ro-swell Park Cancer Institute, Dr. Hol-land journeyed north from Bethesda, Maryland, to Buffalo, New York. His tenure at Roswell Park would be a rich experience for both his research career and his personal life. There, a chance visit by a young doctor would end in

James F. Holland, MDcontinued from page 41

Vincent T. DeVita, MD

Emil J. Freireich, MD

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marriage, forging one of the oncology community’s most accomplished and cherished husband-and-wife teams: James and Jimmie Holland.

“Jim was Chief of Medicine at Ro-swell Park at the time. I was in resi-dency in St. Louis and went to Buffalo to visit a dear woman colleague who was a surgical fellow at Roswell. It was a lucky chance that we met. Our many years together and six children speak

to just how lucky we both were to find each other,” said Jimmie Holland, MD, Wayne E. Chapman Chair in Psy-chiatric Oncology at Memorial Sloan Kettering Cancer Center.

Oncology trailblazer Pierre R. Band, MD, spoke of his time with Dr. Holland at Roswell Park. “I joined the Department of Medicine headed by James F. Holland, MD, at Roswell Park Memorial Institute in Buffalo, New York. I consider Dr. Holland the men-

tor who taught me cancer medicine and who introduced me to two of the main cooperative oncology groups: the Acute Leukemia Group B (subse-quently Cancer and Leukemia Group B) and the Eastern Cooperative On-cology Group (ECOG). During those years, I benefited from Dr. Holland’s pioneering work at what was the fore-front of cancer medicine.”

While Dr. Holland was at Roswell Park, C. Gordon Zubrod, MD, who was Head of NCI’s Division of Can-cer Treatment, recruited him and Emil “Tom” Frei III, MD, establishing a con-tinuing collaboration to test anticancer drugs. “We published the first collab-orative oncology paper in the United States, which appeared in Blood. Fol-

lowing that, the Cancer Chemothera-py National Service Center (CCNSC) was established under the impetus of Mary Lasker, led by Dr. Kenneth Endi-cott, who later became Director of the NCI. It set up a network of cooperative clinical trial groups that evolved across the country under the auspices of the

NCI,” said Dr. Holland.

Going Behind the Iron CurtainAsked about winning the Lasker

Award, Dr. Holland replied, “First off, I am a strong believer that Mary Lasker was this country’s most im-portant person in cancer research.

She felt that cancer awareness need-ed a boost, so in 1972, the Lasker Award was given to clinicians who made progress in treating cancer. About 18 of us won the Lasker; Tom Frei won for Hodgkin lymphoma, and I won for acute leukemia. It was


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Pierre R. Band, MD

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a $2,000 prize, which was big-time money then.”

However, an unexpected mission would take Dr. Holland and his family behind the Iron Curtain, leaving his seat at the Lasker Award ceremony empty. “During the Cold War, Nixon and Brezhnev tried to put aside the notion of dropping atomic bombs on each other and agreed that finding a cure for cancer would be mutually beneficial. So Brezhnev would send a scientist with his family to the United States, and we, in turn, would send a counterpart family to Russia.

Dr. Zubrod enlisted me and others to find a candidate, but no one wanted to go. I was leaving Roswell Park at the time, and after the third call from Dr. Zubrod, I asked Jimmie, ‘how about us?’ She said okay, and off we went with our six kids. I missed the Lasker ceremony, but we had an extraordinary experience for 7 months in the Soviet Union. I lec-tured all over the Soviet Union and was welcomed, even though I came from a contrary political system. I’ve never had better audiences than I had in the Soviet Union—standing room only. As for the family, the three boys had to

sleep in one room, and the three girls in another, and it added to the commu-nity and bonding between them,” said Dr. Holland.

ASCO PresidencyDr. Holland, who served as ASCO

President from 1976 to 1978, admits that he was an early skeptic of ASCO’s true value in the field of oncology. “I did not think it would get to its pres-ent level of extreme value. It started small, like everything. But we have to pay attention to the concept that a small group of dedicated people is the only thing in the world that ever has changed things, and ASCO has changed things,” he said.

Asked to amplify his thoughts on the field that he has dedicated his life’s work to and to the Society that he has been an integral part of, Dr. Holland responded, “Oncologists are occupied

with an unusual kind of medicine, and, as a result, we are exposed to enormous personal stress and strain, because pa-tients we care for are profoundly sick

with potentially fatal diseases. As a group, we deal with the possible mor-tality of those for whom we are respon-sible, far more than physicians of most other specialties. So, an important part of being able to sustain oneself in oncol-ogy is to have the camaraderie of fellow oncologists, kindred souls who have the same experiences, who are facing the same challenges and who under-stand. ASCO has served wonderfully for me and for many others to maintain the recognition that we are all in this long and difficult chore together.”

Still Pushing the BoundariesFinding the etiology of disease is

the pathway to prevention and pos-

sibly cures. Such is the motivation of Dr. Holland’s cutting-edge research. “I see patients on certain days of the week and interact with my laboratory colleagues. We are deeply engrossed in the research that I’ve pursued for 20 years, exploring a virus in human breast cancer that is a ‘kissing cousin’ of the mouse mammary tumor virus, the causative agent for breast cancer in mice. Forty percent of American women who present with breast can-cer have this virus in their tumor, but not in the normal tissue of the same breast, which thus excludes genetic inheritance. It is acquired. We are working hard to fulfill the criteria that will prove the virus is indeed the cause of these breast cancers. It keeps me busy and out of trouble,” said Dr. Holland.

When people open their eyes in the morning, they are greeted with a new day, full of the vagaries and insecuri-ties that come with human life. We are obliged to do something with the day ahead. Dr. Holland goes to work at the hospital and the lab. It’s important that he does, and for that alone, he should serve as an inspiration for every young doctor dreaming of entering the noble field of oncology. n

James F. Holland, MDcontinued from page 43

Dr. Holland has always been a true leader and an inspirational figure, willing to tackle the toughest

problems. On his 90th birthday, he is still challenging the conventional wisdom with his continuing research.

—Emil J. Freireich, MD

Keith Witmer (artist) received his Bachelor’s degree in Fine Arts

from Otis/Parsons School of Design.

He subsequently launched his career in advertising and publication with a com-

Ronald Piana is an independent writer and reporter with more

than 20 years of experience in on-cology communications and pub-lishing. In addition to the profiles published in this special supplemen-

tal issue of The ASCO Post, Ron has written more than 100 news and fea-ture articles, interviews, and profiles for leading medical publications. A native New Yorker, in his ear-lier years Ron lived in Paris before traveling worldwide as a merchant seaman, later working as a laborer, truck driver, chef, and restaurant owner. His life-long boxing aspira-tions were halted after going a round in Brooklyn's infamous Gleason’s Gym with the legendary Roberto Duran on “one thrilling but box-ing career–ending day.” Ron lives in Huntington, New York, with his wife Kristine. n

About the Contributors

manding presence, initially using pen and ink and scratchboard mediums. Working with clients such as FedEx, Apple Computer, Hewlett-Packard, and National Geographic, Keith refined his skills and developed new illustration techniques which combined both tra-ditional and digital mediums. Today, Keith works exclusively with his trusty Stylus and Wacom Tablet to execute every illustration. Keith addresses every portrait with absolute professionalism and uncompromising attention to de-tail. When Keith is not at the drawing board, he can be found on his mountain bike or in a sushi bar somewhere in the beautiful city of Portland, Oregon. n

Keith Witmer

Visit The ASCO Post website at ASCOPost.com

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2015 Novartis 4/15 MAF-1111266

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).Drug InteractionsEffects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent,

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 3. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.

To learn more, visit TAFINLARMEKINISTHCP.com

Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

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Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions

TAFINLAR plus MEKINIST 2 mg

N = 55


N = 54TAFINLAR

N = 53

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests


N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

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Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions


N = 55


N = 54TAFINLAR

N = 53

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests


N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

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ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.


GlaxoSmithKlineResearch Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR: 4BRS

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Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1,2

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1,2

Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

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Overall Response

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+ MEKINIST2 mg once daily

TAFINLAR150 mg twice daily

(N=54)

Major effi cacy outcome: Investigator-assessed overall response rate1,2

Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

10.5 months(95% CI: 7, 15)

Months

(N=54)150 mg twice daily

Effi cacy outcome: Investigator-assessed median duration of response1,2


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Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1,2

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1,2



MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

0

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40

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9%

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Overall Response

54%(95% CI: 40, 67)

Overall Response

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+ MEKINIST2 mg once daily


(N=54)

Major effi cacy outcome: Investigator-assessed overall response rate1,2

Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

10.5 months(95% CI: 7, 15)

Months

(N=54)150 mg twice daily

Effi cacy outcome: Investigator-assessed median duration of response1,2


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New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST.Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.

Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.

Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

The fi rst and only FDA-approved combination therapy

Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST.

Important Safety Information for TAFINLAR and MEKINIST when used in combination


DEMONSTRATED DURABLE RESPONSE RATEDEMONSTRATED DURABLE RESPONSE RATEIN A PHASE II STUDY 1-3




AGENTS. THERAPY.2 1AGENTS. THERAPY.2 1

overallresponse

rate1,2

overallresponse

rate1,2

median durationof response1,2

median durationof response1,2

months(95% CI: 7, 15)

months(95% CI: 5, 7)

(95% CI: 62, 87)

(95% CI: 40, 67)

10.510.510.510.55.65.65.65.6

76%76%76%76%

54%54%as a single agent

Investigator-assessed analysis



MEKINIST2 mg once daily

in combination

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